JP4893620B2 - Amino alcohol derivative - Google Patents

Amino alcohol derivative Download PDF

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JP4893620B2
JP4893620B2 JP2007512362A JP2007512362A JP4893620B2 JP 4893620 B2 JP4893620 B2 JP 4893620B2 JP 2007512362 A JP2007512362 A JP 2007512362A JP 2007512362 A JP2007512362 A JP 2007512362A JP 4893620 B2 JP4893620 B2 JP 4893620B2
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ethyl
amino
sulfonyl
hydroxy
esi
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JP2008513348A5 (en
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浩二 服部
進 戸田
健一 鷲塚
真二 伊藤
大輔 田名部
威亘 荒木
稔 桜井
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Astellas Pharma Inc
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    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
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Abstract

The present invention relates to a compound of the formula [I]: wherein (a), in which —Y—, R4, R5 and R6 are4 R5 each as defined in the description, etc., R1 is hydrogen, halogen, lower alkyl, hydroxy, etc., R2 is hydrogen, lower alkyl or hydroxy(lower)alkyl, R3 is hydrogen or an amino protective group, 20R7 is hydrogen, lower alkyl, cyclo(lower)alkyl, lower R9 alkenyl, —Z—R9 or (b), in which —Z— is —0—, —S—, R9 —SO— or —SO2—, and each R9 is independently hydrogen, lower alkyl, cyclo(lower)alkyl, etc., and R8 is -D-E-R10, in which -D- is —CONHSO2— or —S02NHCO—, E is bond or lower alkylene, and R10 is halogen, cyano, carboxy, etc., or a prodrug thereof or a salt thereof. The compound [I] of the present invention and pharmaceutically acceptable salts thereof are useful for the prophylactic and/or the therapeutic treatment of ulcer, overactive bladder, and the like.

Description

本発明は、ベータ３（β３）アドレナリン性受容体作動薬であって、医薬として有用な新規アミノアルコール誘導体およびそれらの塩に関する。 The present invention relates to novel amino alcohol derivatives and salts thereof which are beta 3 (β 3 ) adrenergic receptor agonists and are useful as pharmaceuticals.

１９９０年６月１４日に発行された国際公開ＷＯ９０／０６２９９は、フェニルエタノールアミン誘導体が、代謝、好ましくは血糖値と体脂肪の低下に対して効力を有することを記載しており、２００２年４月２５日に発行された国際公開ＷＯ０２／３２８９７は、アルファアリールエタノールアミン誘導体がβ３アドレナリン性受容体作動薬として有用であることを記載しており、さらに、２００４年１月８日に発行された国際公開ＷＯ２００４／００２９３９および２００５年７月７日に発行された国際公開ＷＯ２００５／０６１４３３は、アミノアルコール誘導体がβ３アドレナリン性受容体作動薬として有用であることを記載している。 International publication WO 90/06299, issued on June 14, 1990, describes that phenylethanolamine derivatives are effective against metabolism, preferably blood glucose and body fat reduction. International Publication WO 02/32897, published on May 25, describes that alpha arylethanolamine derivatives are useful as β 3 adrenergic receptor agonists, and further published on January 8, 2004. International Publication WO 2004/002939 and International Publication WO 2005/061433 issued on July 7, 2005 describe that amino alcohol derivatives are useful as β 3 adrenergic receptor agonists.

本発明は、β３アドレナリン性受容体作動薬である新規アミノアルコール誘導体およびそれらの塩に関する。 The present invention relates to novel aminoalcohol derivatives that are β 3 adrenergic receptor agonists and salts thereof.

より詳しくは、本発明は、胃腸疾患、潰瘍、過活動膀胱、排尿障害、膵臓炎、肥満症、糖尿病などの治療および／または予防に有用な新規アミノアルコール誘導体およびそれらの塩、それらの製造方法、それらを含有する医薬組成物、ならびにそれらをヒトまたは動物における前記疾患の治療および／または予防に用いる方法に関する。   More specifically, the present invention relates to novel amino alcohol derivatives and salts thereof useful for the treatment and / or prevention of gastrointestinal diseases, ulcers, overactive bladder, dysuria, pancreatitis, obesity, diabetes and the like, and methods for producing them , Pharmaceutical compositions containing them, and methods of using them for the treatment and / or prevention of said diseases in humans or animals.

本発明の一つの目的は、前記疾患の治療および／または予防に有用な新規アミノアルコール誘導体およびそれらの塩を提供することである。   One object of the present invention is to provide novel amino alcohol derivatives and salts thereof useful for the treatment and / or prevention of the above diseases.

本発明の他の目的は、前記のアミノアルコール誘導体およびそれらの塩の製造法を提供することである。   Another object of the present invention is to provide a process for producing the amino alcohol derivatives and salts thereof.

本発明のさらに他の目的は、前記のアミノアルコール誘導体およびそれらの塩を有効成分として含有する医薬組成物を提供することである。   Still another object of the present invention is to provide a pharmaceutical composition containing the amino alcohol derivatives and salts thereof as active ingredients.

本発明のいま一つの目的は、前記のアミノアルコール誘導体およびそれらの塩を用いて、ヒトまたは動物における前記の疾患の治療および／または予防方法を提供することである。   Another object of the present invention is to provide a method for treating and / or preventing the above-mentioned diseases in humans or animals using the above-mentioned amino alcohol derivatives and their salts.

本発明の目的アミノアルコール誘導体は新規であり、下記の式［Ｉ］   The object amino alcohol derivatives of the present invention are novel and have the following formula [I]

Figure 0004893620
Figure 0004893620

［式中、 [Where:

Figure 0004893620
Figure 0004893620

Figure 0004893620
−Ｘ−は
Figure 0004893620
 -X- is

Figure 0004893620
Figure 0004893620

（式中、−Ｙ−は結合、−Ｏ−、−ＮＨ−または−ＣＨ２−、
Ｒ４、Ｒ５およびＲ６は、それぞれ個別に水素、低級アルキルまたはヒドロキシ（低級）アルキルである。）、または (Wherein, -Y- is bond, -O -, - NH- or -CH 2 -,
R 4 , R 5 and R 6 are each independently hydrogen, lower alkyl or hydroxy (lower) alkyl. ), Or

Figure 0004893620
Figure 0004893620

（式中、ｎは０、１または２である。）、
Ｒ１は水素、ハロゲン、低級アルキル、ヒドロキシ、低級アルコキシ、アリールオキシ、ニトロ、アミノ、（モノまたはジ）（低級）アルキルアミノまたはアリールアミノ、
Ｒ２は水素、低級アルキルまたはヒドロキシ（低級）アルキル、
Ｒ３は水素またはアミノ保護基、
Ｒ７は水素、低級アルキル、シクロ（低級）アルキル、低級アルケニル、−Ｚ−Ｒ９または (Wherein n is 0, 1 or 2),
R 1 is hydrogen, halogen, lower alkyl, hydroxy, lower alkoxy, aryloxy, nitro, amino, (mono or di) (lower) alkylamino or arylamino,
R 2 is hydrogen, lower alkyl or hydroxy (lower) alkyl,
R 3 is hydrogen or an amino protecting group,
R 7 is hydrogen, lower alkyl, cyclo (lower) alkyl, lower alkenyl, —Z—R 9 or

Figure 0004893620
Figure 0004893620

（式中、−Ｚ−は−Ｏ−、−Ｓ−、−ＳＯ−または−ＳＯ２−、
各々のＲ９は、個別に水素、低級アルキル、シクロ（低級）アルキル、低級アルケニル、カルバモイル、低級アルキルカルバモイル、低級アルキルスルホニル、アリールまたは複素環基である。）、
Ｒ８は−Ｄ−Ｅ−Ｒ１０（式中、−Ｄ−は−ＣＯＮＨＳＯ２−または−ＳＯ２ＮＨＣＯ−、
Ｅは結合または低級アルキレン、
Ｒ１０はハロゲン、シアノ、カルボキシ、低級アルコキシカルボニル、カルバモイル、低級アルキルカルバモイル、複素環基、−Ｏ−Ｒ１１、−Ｓ−Ｒ１１または (Wherein, -Z- is -O -, - S -, - SO- or -SO 2 -,
Each R 9 is independently hydrogen, lower alkyl, cyclo (lower) alkyl, lower alkenyl, carbamoyl, lower alkylcarbamoyl, lower alkylsulfonyl, aryl or heterocyclic group. ),
R 8 is -D-E-R 10 (wherein -D- is -CONHSO 2 -or -SO 2 NHCO-,
E is a bond or lower alkylene,
R 10 is halogen, cyano, carboxy, lower alkoxycarbonyl, carbamoyl, lower alkylcarbamoyl, heterocyclic group, —O—R 11 , —S—R 11 or

Figure 0004893620
Figure 0004893620

（式中、各々のＲ１１は、個別に水素、低級アルキル、低級アルカノイル、低級アルコキシカルボニルまたはアリール（低級）アルキルである。）である。）、
をそれぞれ意味する。］
で表される化合物またはそのプロドラッグまたはその塩である。 Wherein each R 11 is independently hydrogen, lower alkyl, lower alkanoyl, lower alkoxycarbonyl or aryl (lower) alkyl. ),
Means each. ]
Or a prodrug or salt thereof.

本発明によれば、目的化合物は下記の式で表される諸方法によって製造することができる。
製造法１ According to the present invention, the target compound can be produced by various methods represented by the following formulas.
Manufacturing method 1

Figure 0004893620
Figure 0004893620

Figure 0004893620
Figure 0004893620
製造法２Manufacturing method 2

Figure 0004893620
Figure 0004893620

Figure 0004893620
Figure 0004893620
製造法３Production method 3

Figure 0004893620
Figure 0004893620

Figure 0004893620
Figure 0004893620
製造法４Manufacturing method 4

Figure 0004893620
Figure 0004893620

Figure 0004893620
Figure 0004893620
製造法５Manufacturing method 5

Figure 0004893620
Figure 0004893620

Figure 0004893620
Figure 0004893620

Figure 0004893620
Figure 0004893620
製造法６Manufacturing method 6

Figure 0004893620
Figure 0004893620

Figure 0004893620
（式中、
Figure 0004893620
 (Where

Figure 0004893620
Figure 0004893620

−Ｘ−、Ｒ１、Ｒ２、Ｒ３、Ｒ７、Ｒ８、ＥおよびＲ１０は、それぞれ前記定義の通りであり、
Ｒ３ ａはアミノ保護基、
Ｒ１２は低級アルキル、
Ｙ１は脱離基、
をそれぞれ意味する。）
出発化合物［ＩＩ］、［ＩＩＩ］、［Ｉａ］、［ＩＶ］、［Ｖ］、［ＶＩ］、［Ｉｄ］、［ＶＩＩＩ］および［ＩＸ］のいくつかは新規であり、下記の製造例および実施例に記載の方法または慣用の方法にしたがって製造することができる。 -X-, R 1 , R 2 , R 3 , R 7 , R 8 , E and R 10 are each as defined above;
R 3 a is an amino protecting group,
R 12 is lower alkyl,
Y 1 is a leaving group,
Means each. )
Some of the starting compounds [II], [III], [Ia], [IV], [V], [VI], [Id], [VIII] and [IX] are novel, and the following preparation examples and It can be produced according to the methods described in the examples or conventional methods.

本明細書の以上および以下の記述において、本発明の範囲に包含される種々の定義の好適な例を次に詳細に説明する。   In the foregoing and following description of the present specification, preferred examples of the various definitions encompassed within the scope of the present invention will now be described in detail.

「低級」とは、特記ない限り、炭素原子１ないし８個、好ましくは１ないし７個、より好ましくは１ないし６個、最も好ましくは１ないし４個を有する基を意味する。   “Lower” means a group having 1 to 8, preferably 1 to 7, more preferably 1 to 6, most preferably 1 to 4 carbon atoms, unless otherwise specified.

「低級アルキル」および「ヒドロキシ低級（アルキル）」、「（モノまたはジ）（低級）アルキルアミノ」、「低級アルキルカルバモイル」、「低級アルキルスルホニル」および「アリール（低級）アルキル」における「低級アルキル」部分の好適なものとしては、炭素原子１ないし８個、好ましくは１ないし７個、より好ましくは１ないし６個を有する直鎖または分枝状のもの、たとえばメチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、第二級ブチル、第三級ブチル、ペンチル、イソペンチル、１−メチルペンチル、第三級ペンチル、ネオペンチル、ヘキシル、イソヘキシルなどを挙げることができ、好ましいものとしてはメチル、エチル、プロピル、イソプロピルまたはイソブチルを挙げることができる。   “Lower alkyl” in “lower alkyl” and “hydroxy lower (alkyl)”, “(mono or di) (lower) alkylamino”, “lower alkylcarbamoyl”, “lower alkylsulfonyl” and “aryl (lower) alkyl” Suitable moieties are linear or branched having 1 to 8, preferably 1 to 7, more preferably 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl. , Isobutyl, secondary butyl, tertiary butyl, pentyl, isopentyl, 1-methylpentyl, tertiary pentyl, neopentyl, hexyl, isohexyl, etc., and preferred are methyl, ethyl, propyl, isopropyl Or isobutyl can be mentioned.

「低級アルコキシ」および「低級アルコキシカルボニル」における「低級アルコキシ」部分の好適なものとしては、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、第三級ブトキシ、ペンチルオキシ、第三級ペンチルオキシ、ヘキシルオキシなどを挙げることができ、好ましいものとしてはメトキシまたは第三級ブトキシを挙げることができる。   Suitable examples of the “lower alkoxy” moiety in “lower alkoxy” and “lower alkoxycarbonyl” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentyloxy, tertiary pentyloxy, Hexyloxy and the like can be mentioned, and preferable examples include methoxy or tertiary butoxy.

好適な「低級アルカノイル」としては、ホルミル、アセチル、プロパノイル、ブタノイル、２−メチルプロパノイル、ペンタノイル、２，２−ジメチルプロパノイル、ヘキサノイルなどを挙げることができ、好ましいものとしてはアセチルを挙げることができる。   Suitable “lower alkanoyl” includes formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl and the like, and preferred is acetyl. it can.

好適な「シクロ（低級）アルキル」としては、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチルなどを挙げることができ、好ましいものとしてはシクロ（Ｃ３−Ｃ７）アルキルを、より好ましいものとしてはシクロペンチル、シクロヘキシルまたはシクロヘプチルを挙げることができる。 Suitable “cyclo (lower) alkyl” may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like, with cyclo (C 3 -C 7 ) alkyl being more preferred. Mention may be made of cyclopentyl, cyclohexyl or cycloheptyl.

好適な「低級アルケニル」としては、ビニル、１−（または２−）プロペニル、１−（または２−または３−）ブテニル、１−（または２−または３−または４−）ペンテニル、１−（または２−または３−または４−または５−）ヘキセニル、１−（または２−）メチルビニル、エチルビニル、１−（または２−または３−）メチル−１−（または２−）プロペニル、１−（または２−または３−）エチル−１−（または２−）プロペニル、１−（または２−または３−または４−）メチル−１−（または２−または３−）ブテニルなどを挙げることができ、好ましいものとしてはＣ２−Ｃ４アルケニルを挙げることができる。 Suitable “lower alkenyl” includes vinyl, 1- (or 2-) propenyl, 1- (or 2- or 3-) butenyl, 1- (or 2- or 3- or 4-) pentenyl, 1- ( Or 2- or 3- or 4- or 5-) hexenyl, 1- (or 2-) methylvinyl, ethylvinyl, 1- (or 2- or 3-) methyl-1- (or 2-) propenyl, 1- (Or 2- or 3-) ethyl-1- (or 2-) propenyl, 1- (or 2- or 3- or 4-) methyl-1- (or 2- or 3-) butenyl and the like. can be, preferred are it can be mentioned C 2 -C 4 alkenyl.

好適な「低級アルキレン」としては、炭素原子１ないし６個を有する直鎖または分枝状のアルキレン、たとえばメチレン、エチレン、トリメチレン、２，２−ジメチルトリメチレン、３，３−ジメチルトリメチレン、テトラメチレン、ペンタメチレン、ヘキサメチレン、プロピレンなどを挙げることができ、好ましいものとしては炭素原子１ないし４個を有する直鎖状のアルキレンを挙げることができる。   Suitable “lower alkylene” includes straight-chain or branched alkylene having 1 to 6 carbon atoms such as methylene, ethylene, trimethylene, 2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene, tetra Examples include methylene, pentamethylene, hexamethylene, propylene and the like, and preferable examples include linear alkylene having 1 to 4 carbon atoms.

好適な「ハロゲン」としては、フッ素、塩素、臭素およびヨウ素を挙げることができ、好ましいものとしては、フッ素または塩素を挙げることができる。   Suitable “halogen” may include fluorine, chlorine, bromine and iodine, and preferable examples include fluorine or chlorine.

「アリール」および「アリールオキシ」、「アリールアミノ」および「アリール（低級）アルキル」における「アリール」部分の好適なものとしては、フェニル、ナフチル、インデニル、アントリルなどを挙げることができ、好ましいものとしてはフェニルを挙げることができる。   Preferable examples of the “aryl” moiety in “aryl” and “aryloxy”, “arylamino” and “aryl (lower) alkyl” include phenyl, naphthyl, indenyl, anthryl and the like. Can include phenyl.

好適な「複素環基」は、窒素原子、硫黄原子および酸素原子から選択されるヘテロ原子を少なくとも１個有するものであって、飽和または不飽和の単環式または多環式複素環基を挙げることができ、好ましい複素環基としては、窒素含有複素環基、たとえば窒素原子１ないし４個を有する３ないし６員の不飽和複素単環基、たとえばピロリル、ピロリニル、イミダゾリル、ピラゾリル、ピリジル、ピリミジニル、ピラジニル、ピリダジニル、トリアゾリル［たとえば４Ｈ−１，２，４−トリアゾリル、１Ｈ−１，２，３−トリアゾリル、２Ｈ−１，２，３−トリアゾリルなど］、テトラゾリル［たとえば１Ｈ−テトラゾリル、２Ｈ−テトラゾリルなど］など； 窒素原子１ないし４個を有する３ないし７員の飽和複素単環基［たとえばピロリジニル、イミダゾリジニル、ピペリジル、ピペラジニル、ホモピペラジニルなど］；
窒素原子１ないし５個を有する不飽和縮合複素環基、たとえばインドリル、イソインドリル、インドリジニル、ベンズイミダゾリル、キノリル、イソキノリル、イミダゾピリジル、インダゾリル、ベンゾトリアゾリル、テトラゾロピリダジニル［たとえばテトラゾロ［１，５−ｂ］ピリダジニルなど］、キオキサリニルなど；
酸素原子１個を有する３ないし６員の不飽和複素単環基、たとえばピラニル、フリルなど；
酸素原子１個を有する３ないし６員の飽和複素単環基、たとえば１Ｈ−テトラヒドロピラニル、テトラヒドロフラニルなど；
硫黄原子１ないし２個を有する３ないし６員の不飽和複素単環基、たとえばチエニルなど；
酸素原子１ないし２個および窒素原子１ないし３個を有する３ないし６員の不飽和複素単環基、たとえばオキサゾリル、イソオキサゾリル、オキサジアゾリル［たとえば１，２，４−オキサジアゾリル、１，３，４−オキサジアゾリル、１，２，５−オキサジアゾリルなど］、オキサゾリニル［たとえば２−オキサゾリニルなど］など；
酸素原子１ないし２個および窒素原子１ないし３個を有する３ないし６員の飽和複素単環基［たとえばモルホリニルなど］；
酸素原子１ないし２個および窒素原子１ないし３個を有する不飽和縮合複素環基［たとえばベンゾフラザニル、ベンゾオキサゾリル、ベンゾオキサジアゾリルなど］；
硫黄原子１ないし２個および窒素原子１ないし３個を有する３ないし６員の不飽和複素単環基、たとえばチアゾリル、チアジアゾリル［たとえば１，２，４−チアジアゾリル、１，３，４−チアジアゾリル、１，２，５−チアジアゾリルなど］など；
硫黄原子１ないし２個および窒素原子１ないし３個を有する３ないし６員の飽和複素単環基［たとえばチアゾリジニルなど］；
硫黄原子１ないし２個および窒素原子１ないし３個を有する不飽和縮合複素環基［たとえばベンゾチアゾリル、ベンゾチアジアゾリルなど］；
酸素原子１ないし２個を有する不飽和縮合複素環基［たとえばベンゾフラニル、ベンゾジオキソリル、クロマニルなど］などを挙げることができる。 Suitable “heterocyclic groups” are those having at least one heteroatom selected from a nitrogen atom, a sulfur atom and an oxygen atom, and include saturated or unsaturated monocyclic or polycyclic heterocyclic groups Preferred heterocyclic groups include nitrogen-containing heterocyclic groups such as 3- to 6-membered unsaturated heterocyclic monocyclic groups having 1 to 4 nitrogen atoms such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl , Pyrazinyl, pyridazinyl, triazolyl [eg 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl etc.], tetrazolyl [eg 1H-tetrazolyl, 2H-tetrazolyl Etc.] etc .; 3- to 7-membered saturated heteromonocyclic groups having 1 to 4 nitrogen atoms [eg pyrrolidi Nil, imidazolidinyl, piperidyl, piperazinyl, homopiperazinyl, etc.];
Unsaturated fused heterocyclic groups having 1 to 5 nitrogen atoms such as indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, imidazolidyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [eg tetrazolo [1 , 5-b] pyridazinyl and the like], xoxalinyl and the like;
3-6 membered unsaturated heteromonocyclic groups having one oxygen atom, such as pyranyl, furyl, etc .;
3-6 membered saturated heteromonocyclic groups having one oxygen atom, such as 1H-tetrahydropyranyl, tetrahydrofuranyl and the like;
3 to 6 membered unsaturated heteromonocyclic groups having 1 to 2 sulfur atoms, such as thienyl;
3- to 6-membered unsaturated heteromonocyclic groups having 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as oxazolyl, isoxazolyl, oxadiazolyl [for example 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl , 1,2,5-oxadiazolyl etc.], oxazolinyl [eg 2-oxazolinyl etc.] etc .;
3 to 6 membered saturated heteromonocyclic group having 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [for example, morpholinyl and the like];
Unsaturated condensed heterocyclic groups having 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [for example, benzofurazanyl, benzoxazolyl, benzooxadiazolyl, etc.];
3- to 6-membered unsaturated heteromonocyclic groups having 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as thiazolyl, thiadiazolyl [for example 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1 , 2,5-thiadiazolyl etc.] etc .;
A 3 to 6 membered saturated heteromonocyclic group having 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [eg thiazolidinyl];
Unsaturated condensed heterocyclic groups having 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [eg benzothiazolyl, benzothiadiazolyl, etc.];
Examples thereof include unsaturated condensed heterocyclic groups having 1 to 2 oxygen atoms [for example, benzofuranyl, benzodioxolyl, chromanyl and the like].

好適な「脱離基」としては、ヒドロキシ、ヒドロキシから誘導された反応基などを挙げることができる。   Suitable “leaving group” includes hydroxy, a reactive group derived from hydroxy, and the like.

好適な「ヒドロキシから誘導された反応基」としては、酸残基などを挙げることができる。   Suitable “reactive group derived from hydroxy” includes an acid residue and the like.

好適な「酸残基」としては、ハロゲン［たとえばフッ素、塩素、臭素、ヨウ素］、アシルオキシ［たとえばアセトキシ、トシルオキシ、メシルオキシ、トリフルオロメタンスルホニルオキシなど］などを挙げることができる。   Suitable “acid residues” include halogen [eg, fluorine, chlorine, bromine, iodine], acyloxy [eg, acetoxy, tosyloxy, mesyloxy, trifluoromethanesulfonyloxy, etc.] and the like.

「アミノ保護基」の好適な例としては、通常のアミノ保護基、たとえば置換されたまたは置換されていない低級アルカノイル［たとえばホルミル、アセチル、プロピオニル、トリフルオロアセチルなど］、フタロイル、低級アルコキシカルボニル［たとえば第三級ブトキシカルボニル、第三級アミルオキシカルボニルなど］、置換されたまたは置換されていないアラルキルオキシカルボニル［たとえばベンジルオキシカルボニル、ｐ−ニトロベンジルオキシカルボニルなど］、置換されたまたは置換されていないアレーンスルホニル［たとえばベンゼンスルホニル、トシルなど］、ニトロフェニルスルフェニル、アリール（低級）アルキル［たとえばトリチル、ベンジルなど］などを挙げることができ、好ましいものとしては第三級ブトキシカルボニルを挙げることができる。   Suitable examples of the “amino protecting group” include conventional amino protecting groups such as substituted or unsubstituted lower alkanoyl [eg formyl, acetyl, propionyl, trifluoroacetyl etc.], phthaloyl, lower alkoxycarbonyl [eg Tertiary butoxycarbonyl, tertiary amyloxycarbonyl, etc.], substituted or unsubstituted aralkyloxycarbonyl [eg benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, etc.], substituted or unsubstituted arenes Examples include sulfonyl [eg benzenesulfonyl, tosyl, etc.], nitrophenylsulfenyl, aryl (lower) alkyl [eg trityl, benzyl etc.], etc. Preferred is tertiary butoxy Carbonyl can be mentioned.

目的アミノアルコール誘導体［Ｉ］の好適な塩は、医薬として許容される塩であって、無機酸付加塩［たとえば塩酸塩、臭化水素酸塩、硫酸塩、燐酸塩など］、有機酸付加塩［たとえば蟻酸塩、酢酸塩、トリフルオロ酢酸塩、シュウ酸塩、マレイン酸塩、フマル酸塩、酒石酸塩、クエン酸塩、メタンスルホン酸塩、ベンゼンスルホン酸塩、トルエンスルホン酸塩など］、アルカリ金属塩［たとえばナトリウム塩、カリウム塩など］などの慣用の無毒の塩を挙げることができ、好ましいものとしては塩酸塩を挙げることができる。   Suitable salts of the desired aminoalcohol derivative [I] are pharmaceutically acceptable salts, inorganic acid addition salts [eg hydrochlorides, hydrobromides, sulfates, phosphates, etc.], organic acid addition salts [For example, formate, acetate, trifluoroacetate, oxalate, maleate, fumarate, tartrate, citrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], alkali Conventional non-toxic salts such as metal salts [for example, sodium salts, potassium salts and the like] can be mentioned, and hydrochlorides are preferable.

本発明の目的化合物の製造法１ないし６を次に詳細に説明する。
製造法１
目的化合物［Ｉ］またはその塩は、化合物［ＩＩ］を化合物［ＩＩＩ］またはその塩と反応させることによって製造することができる。 The production methods 1 to 6 of the object compound of the present invention are described in detail below.
Manufacturing method 1
The target compound [I] or a salt thereof can be produced by reacting compound [II] with compound [III] or a salt thereof.

化合物［ＩＩＩ］の好適な塩としては、化合物［Ｉ］で例示したのと同じものを挙げることができる。   Suitable examples of the salt of compound [III] include the same salts as those exemplified for compound [I].

反応は塩基の存在下で行われるのが好ましく、塩基としては、たとえばアルカリ金属炭酸塩［たとえば炭酸ナトリウム、炭酸カリウムなど］、アルカリ土類金属炭酸塩［たとえば炭酸マグネシウム、炭酸カルシウムなど］、アルカリ金属重炭酸塩［たとえば重炭酸ナトリウム、重炭酸カリウムなど］、トリ（低級）アルキルアミン［たとえばトリメチルアミン、トリエチルアミンなど］、ピコリンなどを挙げることができる。   The reaction is preferably carried out in the presence of a base. Examples of the base include alkali metal carbonates [for example, sodium carbonate, potassium carbonate, etc.], alkaline earth metal carbonates [for example, magnesium carbonate, calcium carbonate, etc.], alkali metals Bicarbonates [for example, sodium bicarbonate, potassium bicarbonate and the like], tri (lower) alkylamines [for example, trimethylamine, triethylamine and the like], picoline and the like can be mentioned.

反応は、通常、慣用の溶媒、たとえばアルコール［たとえばメタノール、エタノール、プロパノール、イソプロパノールなど］、ジエチルエーテル、テトラヒドロフラン、ジオキサン、または反応に悪影響を及ぼさない他の有機溶媒中で行われる。   The reaction is usually performed in a conventional solvent, such as an alcohol [eg, methanol, ethanol, propanol, isopropanol, etc.], diethyl ether, tetrahydrofuran, dioxane, or other organic solvents that do not adversely affect the reaction.

反応温度は特に限定されず、反応は、冷却ないし加熱下で行うことができる。
製造法２
目的化合物［Ｉｂ］またはその塩は、化合物［Ｉａ］またはその塩をアミノ保護基の脱離反応に付すことによって製造することができる。 The reaction temperature is not particularly limited, and the reaction can be performed under cooling or heating.
Manufacturing method 2
The target compound [Ib] or a salt thereof can be produced by subjecting the compound [Ia] or a salt thereof to an elimination reaction of an amino protecting group.

化合物［Ｉａ］および［１ｂ］の好適な塩としては、化合物［Ｉ］で例示したのと同じものを挙げることができる。   Suitable salts of the compounds [Ia] and [1b] may be the same as those exemplified for the compound [I].

この反応は、下記の実施例３と同様の方法にしたがって実施することができる。
製造法３
目的化合物［Ｉｃ］またはその塩は、化合物［ＩＶ］またはその塩を化合物［Ｖ］またはその塩と反応させることによって製造することができる。 This reaction can be carried out according to the same method as in Example 3 below.
Production method 3
The target compound [Ic] or a salt thereof can be produced by reacting the compound [IV] or a salt thereof with the compound [V] or a salt thereof.

化合物［Ｉｃ］、［ＩＶ］および［Ｖ］の好適な塩としては、化合物［Ｉ］で例示したのと同じものを挙げることができる。   Suitable salts of the compounds [Ic], [IV] and [V] may be the same as those exemplified for the compound [I].

この反応は、下記の実施例２と同様の方法にしたがって実施することができる。
製造法４
目的化合物［Ｉｃ］またはその塩は、化合物［ＩＶ］またはその塩を化合物［ＶＩ］またはその塩と反応させることによって製造することができる。 This reaction can be carried out according to the same method as in Example 2 below.
Manufacturing method 4
The target compound [Ic] or a salt thereof can be produced by reacting compound [IV] or a salt thereof with compound [VI] or a salt thereof.

化合物［Ｉｃ］、「ＩＶ］および［ＶＩ］の好適な塩としては、化合物［Ｉ］で例示したのと同じものを挙げることができる。   Suitable salts of the compounds [Ic], “IV] and [VI] may be the same as those exemplified for the compound [I].

この反応は、下記の製造例４３と同様の方法にしたがって実施することができる。
製造法５
目的化合物［Ｉｆ］またはその塩は、化合物［Ｉｄ］またはその塩を脱エステル化反応に付し、生じた化合物［Ｉｅ］またはその塩を化合物［ＶＩＩ］またはその塩と反応させることによって製造することができる。 This reaction can be carried out according to the same method as in Production Example 43 below.
Manufacturing method 5
The target compound [If] or a salt thereof is produced by subjecting the compound [Id] or a salt thereof to a deesterification reaction and reacting the resulting compound [Ie] or a salt thereof with the compound [VII] or a salt thereof. be able to.

化合物［Ｉｆ］、［Ｉｄ］、［Ｉｅ］および［ＶＩＩ］の好適な塩としては、化合物［Ｉ］で例示したのと同じものを挙げることができる。   Suitable salts of the compounds [If], [Id], [Ie] and [VII] may be the same as those exemplified for the compound [I].

これらの反応は、下記の製造例３および実施例１１と同様の方法にしたがって実施することができる。
製造法６
目的化合物［Ｉｇ］またはその塩は、化合物［ＶＩＩＩ］またはその塩を化合物［ＩＸ］またはその塩と反応させることによって製造することができる。 These reactions can be carried out in the same manner as in Production Example 3 and Example 11 below.
Manufacturing method 6
The target compound [Ig] or a salt thereof can be produced by reacting the compound [VIII] or a salt thereof with the compound [IX] or a salt thereof.

化合物［Ｉｇ］、［ＶＩＩＩ］および［ＩＸ］の好適な塩としては、化合物［Ｉ］で例示したのと同じものを挙げることができる。   Suitable salts of the compounds [Ig], [VIII] and [IX] may be the same as those exemplified for the compound [I].

この反応は、下記の実施例１８と同様の方法にしたがって実施することができる。   This reaction can be carried out in the same manner as in Example 18 described below.

上記の製造法にしたがって得られた化合物は、粉砕、再結晶、カラムクロマトグラフィー、再沈殿などの慣用の方法で分離・精製でき、必要に応じて、慣用の方法で所望の塩に転換できる。   The compound obtained according to the above production method can be separated and purified by a conventional method such as pulverization, recrystallization, column chromatography, reprecipitation, etc., and can be converted into a desired salt by a conventional method, if necessary.

化合物［Ｉ］および他の化合物は、不斉炭素原子に基づく立体異性体を１個またはそれ以上有することがあるが、これらの異性体およびそれらの混合物のすべてもまた本発明の範囲に含まれる。   Compound [I] and other compounds may have one or more stereoisomers based on asymmetric carbon atoms, but all of these isomers and mixtures thereof are also included in the scope of the present invention. .

目的化合物［Ｉ］の異性化または転位が、光、酸、塩基などの影響により生じることがあるが、この異性化または転位の結果として得られる化合物もまた本発明の範囲に含まれる。   The isomerization or rearrangement of the target compound [I] may occur due to the influence of light, acid, base, etc., and the compounds obtained as a result of this isomerization or rearrangement are also included in the scope of the present invention.

さらに、目的化合物［Ｉ］の溶媒和形態［たとえば水和物など］および化合物［Ｉ］の結晶のいかなる形態もまた本発明の範囲に含まれる。   Furthermore, solvated forms [for example, hydrates and the like] of the target compound [I] and any form of crystals of the compound [I] are also included in the scope of the present invention.

目的化合物［Ｉ］またはその塩は、ヒトまたは動物における胃腸疾患の治療および／または予防に有用であり、より詳しくは、過敏性腸症候群、胃炎、胃潰瘍、十二指腸潰瘍、腸炎、胆嚢症、胆管炎、尿路結石などの場合における痙攣または運動機能亢進症の治療および／または予防；胃潰瘍、十二指腸潰瘍、消化性潰瘍などの潰瘍の治療および／または予防；神経性頻尿症、神経因性膀胱機能障害、夜間頻尿症、不安定膀胱、膀胱痙攣、慢性膀胱炎、慢性前立腺炎、前立腺肥大症などの過活動膀胱の治療および／または予防；緊張性尿失禁、急迫性尿失禁、混合性尿失禁、機能性尿失禁、溢流性尿失禁などの排尿障害の治療および／または予防；膵臓炎、肥満症、糖尿病、糖尿、高脂血症、高血圧症、アテローム性動脈硬化症、緑内障、メランコリー、鬱病などの治療および／または予防；インスリン耐性を要因とする疾患（たとえば高血圧症、インスリン過剰血症など）の治療および／または予防；神経性炎症の治療および／または予防；ならびに消耗状態の軽減などに有用である。   The target compound [I] or a salt thereof is useful for the treatment and / or prevention of gastrointestinal diseases in humans or animals, and more specifically, irritable bowel syndrome, gastritis, gastric ulcer, duodenal ulcer, enteritis, cholecystitis, cholangitis Treatment and / or prevention of convulsions or hypermotor in cases such as urinary tract stones; treatment and / or prevention of ulcers such as gastric ulcer, duodenal ulcer, peptic ulcer; neurogenic urinary frequency, neurogenic bladder function Treatment and / or prevention of overactive bladder such as disability, nocturia, unstable bladder, bladder spasm, chronic cystitis, chronic prostatitis, benign prostatic hyperplasia; stress urinary incontinence, urge incontinence, mixed urine Treatment and / or prevention of dysuria such as incontinence, functional urinary incontinence, overflow urinary incontinence; pancreatitis, obesity, diabetes, diabetes, hyperlipidemia, hypertension, atherosclerosis, glaucoma, Treatment and / or prophylaxis such as Ncory, depression, etc .; Treatment and / or prevention of diseases caused by insulin resistance (eg hypertension, hyperinsulinemia, etc.); Treatment and / or prevention of neurogenic inflammation; Useful for mitigation.

さらに、β３アドレナリン性受容体作動薬は、哺乳類においてトリグリセリドおよびコレステロールレベルを下げ、高密度リポ蛋白レベルを上げることが知られている（米国特許Ｎｏ．５，４５１，６７７）。したがって、目的化合物［Ｉ］は、高トリグリセリド血症、高コレステロール血症などの症状の治療および／または予防、高密度リポ蛋白レベルの低下、さらにはアテローム硬化性疾患および循環器疾患ならびに関連症状の治療に有用である。 In addition, β 3 adrenergic receptor agonists are known to lower triglyceride and cholesterol levels and increase high density lipoprotein levels in mammals (US Pat. No. 5,451,677). Therefore, the target compound [I] is used for the treatment and / or prevention of symptoms such as hypertriglyceridemia and hypercholesterolemia, the reduction of high-density lipoprotein levels, and atherosclerotic and cardiovascular diseases and related symptoms. Useful for treatment.

さらに、目的化合物［Ｉ］は、子宮収縮の抑制、早期分娩の防止および月経困難症の治療および予防に有用である。   Furthermore, the target compound [I] is useful for suppressing uterine contraction, preventing premature labor, and treating and preventing dysmenorrhea.

また、目的化合物［Ｉ］は、塩酸プロピベリン、塩酸オキシブチニン、塩酸フラボキセイト、酒石酸トルテロジンなどの過活動膀胱用抗コリン剤と共に用いた場合、強力な抗過活動膀胱作用を発揮すると予想される。   In addition, the target compound [I] is expected to exert a strong anti-overactive bladder action when used with an anticholinergic agent for overactive bladder such as propiverine hydrochloride, oxybutynin hydrochloride, flavoxate hydrochloride, tolterodine tartrate and the like.

治療のためには、本発明の化合物（Ｉ）および医薬として許容されるその塩を、前記化合物の一つを有効成分として、経口、非経口、局所塗布を含む外用、腸内、静脈内、筋肉内、吸入、鼻内、関節内、脊髄内、経気管または経眼投与に適した有機または無機の固体または液体の賦形剤などの医薬として許容される担体と共に含有する医薬製剤の形で用いることができる。前記医薬製剤は、カプセル剤、錠剤、ペレット剤、糖剤、粉末剤、顆粒剤、坐剤、軟膏剤、クリーム剤、ローション剤、吸入剤、注射剤、パップ剤、ゲル剤、テープ剤、点眼薬、液剤、シロップ剤、エアロゾル剤、懸濁剤、乳剤などの固形、半固形または液状であってもよい。必要に応じて、補助剤、安定化剤、湿潤剤または乳化剤、緩衝剤および他の常用添加剤を前記医薬製剤に配合してもよい。   For treatment, the compound (I) of the present invention and a pharmaceutically acceptable salt thereof, one of the compounds as an active ingredient, oral, parenteral, topical application including topical application, enteral, intravenous, In the form of a pharmaceutical formulation containing with a pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for intramuscular, inhalation, intranasal, intraarticular, intraspinal, intratracheal or ocular administration Can be used. The pharmaceutical preparations are capsules, tablets, pellets, dragees, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, poultices, gels, tapes, eye drops It may be solid, semi-solid or liquid such as medicine, liquid, syrup, aerosol, suspension, emulsion and the like. If necessary, adjuvants, stabilizers, wetting or emulsifying agents, buffers and other conventional additives may be incorporated into the pharmaceutical preparation.

化合物（Ｉ）の用量は、患者の年令および症状によっても変動するが、化合物（Ｉ）の約０．１ｍｇ、１ｍｇ、１０ｍｇ、５０ｍｇ、１００ｍｇ、２５０ｍｇ、５００ｍｇおよび１０００ｍｇを平均１回量として用いれば、潰瘍、過活動膀胱、排尿障害などの疾患の治療に有効であろう。一般的には、０．１ｍｇ／体ないし約１０００ｍｇ／体の範囲の量を１日当たり投与すればよい。   The dose of Compound (I) varies depending on the age and symptoms of the patient, but an average dose of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of Compound (I) is used. For example, it may be effective in treating diseases such as ulcers, overactive bladder and dysuria. In general, an amount in the range of 0.1 mg / body to about 1000 mg / body may be administered per day.

ヒトまたは動物における前記疾患の予防および治療のための化合物［Ｉ］の有用性を示すために、化合物［Ｉ］の代表的化合物を、下記の薬学試験にしたがって試験した。
試験
麻酔したイヌにおけるカルバコールによって誘発された膀胱内圧の増加に対する効力
試験化合物
（１） ３−（シクロヘキシルオキシ）−Ｎ−［（２−ヒドロキシエチル）スルホニル］−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エチル］−４−ビフェニルカルボキサミド塩酸塩（下記の実施例１−（８）の目的化合物）
試験方法
体重８．０〜１５．０ｋｇの雌性ビーグル犬を２４時間絶食させ、ハロタン麻酔下に保持した。１２Ｆフォーリーカテーテルを、水溶性ゼリーで潤滑し、尿道口に挿入し、バルーン先端が十分に膀胱内部に位置するまで約１０ｃｍ進入させた。次に、バルーンを５ｍｌの大気で膨張させ、膀胱頚で感じる最初の抵抗箇所までカテーテルを徐々に後退させた。カテーテルを通して尿を完全に排出し、３０ｍｌの生理食塩水を注入した。カテーテルを圧力トランスジューサーに接続し、膀胱内圧（ＩＶＰ）を連続的に記録した。カルバコール（１．８μｇ／ｋｇ）投与の３０分前に、試験化合物を静脈注射した。試験化合物によるＩＶＰ増加阻害率を、ＩＶＰａ（試験化合物投与後にカルバコールによって誘発されたＩＶＰの増加）をＩＶＰｂ（試験化合物投与直前にカルバコールによって誘発されたＩＶＰの増加）で割算して計算した。
試験結果 In order to demonstrate the usefulness of Compound [I] for the prevention and treatment of the above diseases in humans or animals, representative compounds of Compound [I] were tested according to the following pharmaceutical tests.
Efficacy against carbachol-induced increase in intravesical pressure in test anesthetized dogs
Test compound (1) 3- (cyclohexyloxy) -N-[(2-hydroxyethyl) sulfonyl] -4 ′-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethyl]- 4-biphenylcarboxamide hydrochloride (target compound of Example 1- (8) below)
Test Method Female beagle dogs weighing 8.0-15.0 kg were fasted for 24 hours and kept under halothane anesthesia. A 12F Foley catheter was lubricated with water-soluble jelly, inserted into the urethral orifice, and allowed to enter approximately 10 cm until the balloon tip was sufficiently located inside the bladder. The balloon was then inflated with 5 ml of air and the catheter was slowly retracted to the first resistance point felt in the bladder neck. The urine was completely drained through the catheter and 30 ml of physiological saline was injected. The catheter was connected to a pressure transducer and intravesical pressure (IVP) was continuously recorded. Test compounds were injected intravenously 30 minutes before carbachol (1.8 μg / kg) administration. The inhibition rate of increase in IVP by the test compound was calculated by dividing IVPa (increase in IVP induced by carbachol after administration of the test compound) by IVPb (increase in IVP induced by carbachol immediately before administration of the test compound).
Test results

Figure 0004893620
Figure 0004893620

目的化合物［Ｉ］の好ましい例としては、以下のものを挙げることができる。   Preferable examples of the target compound [I] include the following.

−Ｘ−が   -X-

Figure 0004893620
Figure 0004893620

（式中、−Ｙ−は結合、−Ｏ−、−ＮＨ−または−ＣＨ２−、
Ｒ４、Ｒ５およびＲ６は、それぞれ個別に水素、低級アルキル（より好ましくはＣ１−Ｃ４アルキル）またはヒドロキシ（低級）アルキル（より好ましくはヒドロキシ（Ｃ１−Ｃ４）アルキル）である。）、
を意味する。 (Wherein, -Y- is bond, -O -, - NH- or -CH 2 -,
R 4 , R 5 and R 6 are each independently hydrogen, lower alkyl (more preferably C 1 -C 4 alkyl) or hydroxy (lower) alkyl (more preferably hydroxy (C 1 -C 4 ) alkyl). . ),
Means.

目的化合物［Ｉ］のより好ましい例としては、以下のものを挙げることができる。   More preferable examples of the target compound [I] include the following.

Ｒ１が水素、ハロゲン（より好ましくはフッ素または塩素）、ニトロまたはアミノ、
Ｒ２が水素または低級アルキル（より好ましくはＣ１−Ｃ４アルキル、最も好ましくはメチル）、
Ｒ３が水素、
Ｒ７が水素、低級アルキル（より好ましくはＣ１−Ｃ４アルキル、最も好ましくはイソプロピルまたはイソブチル）、シクロ（低級）アルキル（より好ましくはシクロ（Ｃ３−Ｃ６）アルキル）、最も好ましくはシクロペンチル）、−Ｚ−Ｒ９または R 1 is hydrogen, halogen (more preferably fluorine or chlorine), nitro or amino,
R 2 is hydrogen or lower alkyl (more preferably C 1 -C 4 alkyl, most preferably methyl),
R 3 is hydrogen,
R 7 is hydrogen, lower alkyl (more preferably C 1 -C 4 alkyl, most preferably isopropyl or isobutyl), cyclo (lower) alkyl (more preferably cyclo (C 3 -C 6 ) alkyl), most preferably cyclopentyl. ), -ZR 9 or

Figure 0004893620
Figure 0004893620

（式中、−Ｚ−は−Ｏ−、−Ｓ−、−ＳＯ−または−ＳＯ２−、
各々のＲ９は、個別に水素、低級アルキル（より好ましくはＣ１−Ｃ４アルキル、最も好ましくはプロピル、イソプロピルまたはイソブチル）またはシクロ（低級）アルキル（より好ましくはシクロ（Ｃ３−Ｃ６）アルキル、最も好ましくはシクロペンチル、シクロヘキシルまたはシクロヘプチル）である。）、
Ｒ８が−Ｄ−Ｅ−Ｒ１０（式中、−Ｄ−は−ＣＯＮＨＳＯ２−または−ＳＯ２ＮＨＣＯ−、
Ｅは結合または低級アルキレン（より好ましくはＣ１−Ｃ４アルキレン、最も好ましくはメチレン、エチレン、トリメチレン、３，３−ジメチルトリメチレンまたはテトラメチレン）、
Ｒ１０はハロゲン、シアノ、カルボキシ、低級アルコキシカルボニル（より好ましくはＣ１−Ｃ４アルコキシカルボニル、最も好ましくはメトキシカルボニル）、カルバモイル、ピリジル、−Ｏ−Ｒ１１または (Wherein, -Z- is -O -, - S -, - SO- or -SO 2 -,
Each R 9 is independently hydrogen, lower alkyl (more preferably C 1 -C 4 alkyl, most preferably propyl, isopropyl or isobutyl) or cyclo (lower) alkyl (more preferably cyclo (C 3 -C 6 )). Alkyl, most preferably cyclopentyl, cyclohexyl or cycloheptyl). ),
R 8 is -D-E-R 10 (wherein -D- is -CONHSO 2 -or -SO 2 NHCO-,
E is a bond or lower alkylene (more preferably C 1 -C 4 alkylene, most preferably methylene, ethylene, trimethylene, 3,3-dimethyltrimethylene or tetramethylene),
R 10 is halogen, cyano, carboxy, lower alkoxycarbonyl (more preferably C 1 -C 4 alkoxycarbonyl, most preferably methoxycarbonyl), carbamoyl, pyridyl, —O—R 11 or

Figure 0004893620
Figure 0004893620

（式中、各々のＲ１１は、個別に水素、低級アルキル（より好ましくはＣ１−Ｃ４アルキル、最も好ましくはメチルまたはエチル）、低級アルカノイル（より好ましくはＣ１−Ｃ４アルカノイル、最も好ましくはアセチル）または低級アルコキシカルボニル（より好ましくはＣ１−Ｃ４アルコキシカルボニル、最も好ましくは第三級ブトキシカルボニル）である。）である。）、
をそれぞれ意味する。 Wherein each R 11 is independently hydrogen, lower alkyl (more preferably C 1 -C 4 alkyl, most preferably methyl or ethyl), lower alkanoyl (more preferably C 1 -C 4 alkanoyl, most preferably Is acetyl) or lower alkoxycarbonyl (more preferably C 1 -C 4 alkoxycarbonyl, most preferably tertiary butoxycarbonyl). ),
Means each.

目的化合物［Ｉ］のさらに好ましい例としては、以下のものを挙げることができる。   More preferable examples of the target compound [I] include the following.

−Ｘ−が   -X-

Figure 0004893620
Figure 0004893620


（式中、−Ｙ−は結合、−Ｏ−、−ＮＨ−または−ＣＨ２−、
Ｒ４、Ｒ５およびＲ６は、それぞれ水素である。）、
Ｒ７が低級アルキル（より好ましくはＣ１−Ｃ４アルキル、最も好ましくはイソプロピルまたはイソブチル）、シクロ（低級）アルキル（より好ましくはシクロ（Ｃ３−Ｃ６）アルキル）、最も好ましくはシクロペンチル）、−Ｚ−Ｒ９または
(Wherein, -Y- is bond, -O -, - NH- or -CH 2 -,
R 4 , R 5 and R 6 are each hydrogen. ),
R 7 is lower alkyl (more preferably C 1 -C 4 alkyl, most preferably isopropyl or isobutyl), cyclo (lower) alkyl (more preferably cyclo (C 3 -C 6 ) alkyl), most preferably cyclopentyl), -ZR 9 or

Figure 0004893620
Figure 0004893620


（式中、−Ｚ−は−Ｏ−または−Ｓ−、
各々のＲ９は、個別に低級アルキルまたはシクロ（低級）アルキル（より好ましくはＣ１−Ｃ４アルキル、最も好ましくはプロピル、イソプロピルまたはイソブチル）またはシクロ（低級）アルキル（より好ましくはシクロ（Ｃ３−Ｃ６）アルキル、最も好ましくはシクロペンチル、シクロヘキシルまたはシクロヘプチル）である。）、
Ｒ８が−Ｄ−Ｅ−Ｒ１０（式中、−Ｄ−は−ＣＯＮＨＳＯ２−または−ＳＯ２ＮＨＣＯ−、
Ｅは結合または低級アルキレン（より好ましくはＣ１−Ｃ４アルキレン、最も好ましくはメチレン、エチレン、トリメチレン、３，３−ジメチルトリメチレンまたはテトラメチレン）、
Ｒ１０はシアノ、カルボキシ、カルバモイル、ピリジル、−Ｏ−Ｒ１１または
(In the formula, -Z- represents -O- or -S-,
Each R 9 is independently a lower alkyl or cyclo (lower) alkyl (more preferably C 1 -C 4 alkyl, most preferably propyl, isopropyl or isobutyl) or cyclo (lower) alkyl (more preferably cyclo (C 3) -C 6) alkyl, most preferably cyclopentyl, cyclohexyl or cycloheptyl). ),
R 8 is -D-E-R 10 (wherein -D- is -CONHSO 2 -or -SO 2 NHCO-,
E is a bond or lower alkylene (more preferably C 1 -C 4 alkylene, most preferably methylene, ethylene, trimethylene, 3,3-dimethyltrimethylene or tetramethylene),
R 10 is cyano, carboxy, carbamoyl, pyridyl, —O—R 11 or

Figure 0004893620
Figure 0004893620

（式中、各々のＲ１１は、個別に水素、低級アルキル（より好ましくはＣ１−Ｃ４アルキル、最も好ましくはメチルまたはエチル）である。）である。）、
をそれぞれ意味する。 Wherein each R 11 is independently hydrogen, lower alkyl (more preferably C 1 -C 4 alkyl, most preferably methyl or ethyl). ),
Means each.

以下の製造例および実施例は、本発明を説明するために示したものである。前記の「カルバモイル」基を、以下の記述において「アミノカルボニル」基と称することがある。 The following production examples and examples are given to illustrate the present invention. The aforementioned “carbamoyl” group may be referred to as an “aminocarbonyl” group in the following description.

製造例１
［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］［２−［３’−（イソプロポキシ）−４’−［［（メチルスルホニル）アミノ］カルボニル］−４−ビフェニリル］エチル］カルバミン酸第三級ブチル（６５ｍｇ）の１，４−ジオキサン（２ｍｌ）中の溶液に、塩酸／１，４−ジオキサン溶液（４Ｎ、４ｍｌ）を室温で加え、混合物を同温で２．５時間攪拌した。混合物から溶媒を減圧留去し、４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エチル］−３−イソプロポキシ−Ｎ−（メチルスルホニル）−４−ビフェニルカルボキサミド塩酸塩（３８ｍｇ）を得た。
NMR (200 MHz, DMSO-d6, δ): 1.37 (6H, d, J=5.7Hz), 3.06-3.25 (6H, m), 3.38 (3H, s), 4.97-5.00 (2H, m), 6.23 (1H, br s), 7.28-7.48 (9H, m), 7.72-7.79 (3H, m)
(+)ESI-MS (m/z): 497 (M+H)+ Production Example 1
[(2R) -2-hydroxy-2-phenylethyl] [2- [3 ′-(isopropoxy) -4 ′-[[(methylsulfonyl) amino] carbonyl] -4-biphenylyl] ethyl] carbamic acid tertiary To a solution of primary butyl (65 mg) in 1,4-dioxane (2 ml) was added hydrochloric acid / 1,4-dioxane solution (4N, 4 ml) at room temperature and the mixture was stirred at the same temperature for 2.5 hours. The solvent was distilled off from the mixture under reduced pressure, and 4 ′-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethyl] -3-isopropoxy-N- (methylsulfonyl) -4-biphenyl was removed. Carboxamide hydrochloride (38 mg) was obtained.
NMR (200 MHz, DMSO-d 6 , δ): 1.37 (6H, d, J = 5.7Hz), 3.06-3.25 (6H, m), 3.38 (3H, s), 4.97-5.00 (2H, m), 6.23 (1H, br s), 7.28-7.48 (9H, m), 7.72-7.79 (3H, m)
(+) ESI-MS (m / z): 497 (M + H) +

実施例１
下記の化合物を製造例１と同様の方法にしたがって得た。
（１） ４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エチル］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−３−イソプロポキシ−４−ビフェニルカルボキサミド塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.36 (6H, d, J=6.0Hz), 1.81-1.95 (2H, m), 2.99-2.73 (6H, m), 3.47-3.58 (4H, m), 4.75 (1H, t, J=5.0Hz), 4.91-5.05 (2H, m), 6.24 (1H, d, J=4.0Hz), 7.31-7.43 (9H, m), 7.68-7.76 (3H, m)
(+)ESI-MS (m/z): 541 (M+H)+ Example 1
The following compound was obtained according to the same method as in Production Example 1.
(1) 4 ′-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethyl] -N-[(3-hydroxypropyl) sulfonyl] -3-isopropoxy-4-biphenylcarboxamide Hydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 1.36 (6H, d, J = 6.0Hz), 1.81-1.95 (2H, m), 2.99-2.73 (6H, m), 3.47-3.58 (4H, m ), 4.75 (1H, t, J = 5.0Hz), 4.91-5.05 (2H, m), 6.24 (1H, d, J = 4.0Hz), 7.31-7.43 (9H, m), 7.68-7.76 (3H, m)
(+) ESI-MS (m / z): 541 (M + H) +

（２） ４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エチル］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−３−（イソプロピルチオ）−４−ビフェニルカルボキサミド塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.25 (6H, d, J=6.5Hz), 1.85-1.99 (2H, m), 3.02-3.27 (6H, m), 3.49-3.58 (4H, m), 3.62-3.72 (1H, m), 4.76 (1H, br s), 4.95-5.04 (1H, m), 6.23 (1H, d, J=4Hz), 7.31-7.42 (7H, m), 7.55-7.64 (2H, m), 7.70-7.74 (3H, m), 8.92 (1H, br s), 9.26 (1H, br s), 12.14 (1H, s)
(-)ESI-MS (m/z): 555 (M-H)- (2) 4 ′-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethyl] -N-[(3-hydroxypropyl) sulfonyl] -3- (isopropylthio) -4- Biphenyl carboxamide hydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 1.25 (6H, d, J = 6.5Hz), 1.85-1.99 (2H, m), 3.02-3.27 (6H, m), 3.49-3.58 (4H, m ), 3.62-3.72 (1H, m), 4.76 (1H, br s), 4.95-5.04 (1H, m), 6.23 (1H, d, J = 4Hz), 7.31-7.42 (7H, m), 7.55- 7.64 (2H, m), 7.70-7.74 (3H, m), 8.92 (1H, br s), 9.26 (1H, br s), 12.14 (1H, s)
(-) ESI-MS (m / z): 555 (MH) -

（３） ３−（シクロヘキシルオキシ）−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エチル］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４−ビフェニルカルボキサミド塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.34-2.01 (12H, m), 2.99-3.27 (6H, m), 3.46-3.59 (4H, m), 4.71-4.84 (2H, m), 4.94-5.04 (1H, m), 6.23 (1H, d, J=3.5Hz), 7.32-7.43 (9H, m), 7.71-7.75 (3H, m)
(-)ESI-MS (m/z): 579 (M-H)- (3) 3- (Cyclohexyloxy) -4 '-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethyl] -N-[(3-hydroxypropyl) sulfonyl] -4- Biphenyl carboxamide hydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 1.34-2.01 (12H, m), 2.99-3.27 (6H, m), 3.46-3.59 (4H, m), 4.71-4.84 (2H, m), 4.94 -5.04 (1H, m), 6.23 (1H, d, J = 3.5Hz), 7.32-7.43 (9H, m), 7.71-7.75 (3H, m)
(-) ESI-MS (m / z): 579 (MH) -

（４） ３−（シクロヘキシルオキシ）−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エチル］−４−ビフェニルカルボキサミド二塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.35-2.02 (12H, m), 3.05-3.39 (6H, m), 3.48-3.60 (4H, m), 4.75-4.87 (1H, m), 5.27-5.35 (1H, m), 7.33-7.44 (4H, m), 7.71-7.75 (3H, m), 7.98 (1H, dd, J=5.5, 8.5Hz), 8.49 (1H, d, J=8.5Hz), 8.83-8.91 (2H, m), 9.30 (1H, br s), 9.41 (1H, br s), 11.18 (1H, s)
(-)ESI-MS (m/z): 580 (M-H)- (4) 3- (Cyclohexyloxy) -N-[(3-hydroxypropyl) sulfonyl] -4 ′-[2-[[(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] ethyl ] -4-Biphenylcarboxamide dihydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 1.35-2.02 (12H, m), 3.05-3.39 (6H, m), 3.48-3.60 (4H, m), 4.75-4.87 (1H, m), 5.27 -5.35 (1H, m), 7.33-7.44 (4H, m), 7.71-7.75 (3H, m), 7.98 (1H, dd, J = 5.5, 8.5Hz), 8.49 (1H, d, J = 8.5Hz ), 8.83-8.91 (2H, m), 9.30 (1H, br s), 9.41 (1H, br s), 11.18 (1H, s)
(-) ESI-MS (m / z): 580 (MH) -

（５） ３−（シクロヘキシルオキシ）−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エチル］−Ｎ−［（２−メトキシエチル）スルホニル］−４−ビフェニルカルボキサミド二塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.31-2.04 (10H, m), 3.04-3.50 (6H, m), 3.23 (3H, s), 3.72-3.84 (4H, m), 4.78-4.89 (1H, m), 5.27-5.37 (1H, m), 7.34-7.45 (4H, m), 7.68-7.79 (3H, m), 8.00 (1H, dd, J=5.5, 8.4Hz), 8.51 (1H, d, J=8.4Hz), 8.83-8.92 (2H, m), 9.33 (1H, br s), 9.45 (1H, br s), 11.19 (1H, s)
(-)ESI-MS (m/z): 580 (M-H)- (5) 3- (Cyclohexyloxy) -4 ′-[2-[[(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] ethyl] -N-[(2-methoxyethyl) sulfonyl ] -4-Biphenylcarboxamide dihydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 1.31-2.04 (10H, m), 3.04-3.50 (6H, m), 3.23 (3H, s), 3.72-3.84 (4H, m), 4.78-4.89 (1H, m), 5.27-5.37 (1H, m), 7.34-7.45 (4H, m), 7.68-7.79 (3H, m), 8.00 (1H, dd, J = 5.5, 8.4Hz), 8.51 (1H , d, J = 8.4Hz), 8.83-8.92 (2H, m), 9.33 (1H, br s), 9.45 (1H, br s), 11.19 (1H, s)
(-) ESI-MS (m / z): 580 (MH) -

（６） ３−（シクロヘキシルオキシ）−Ｎ−［（２−ヒドロキシエチル）スルホニル］−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エチル］−４−ビフェニルカルボキサミド二塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.30-2.01 (10H, m), 3.02-3.49 (6H, m), 3.67 (2H, t, J=6.0Hz), 3.84 (2H, t, J=5.8Hz), 4.75-4.89 (1H, m), 5.26-5.37 (1H, m), 7.32-7.45 (4H, m), 7.69-7.82 (3H, m), 7.97 (1H, d, J=5.4Hz), 8.5 (1H, d, J=8.0Hz), 8.82-8.93 (2H, m), 9.31 (1H, br s), 9.43 (1H, br s), 11.1 (1H, br s)
(-)ESI-MS (m/z): 566 (M-H)- (6) 3- (Cyclohexyloxy) -N-[(2-hydroxyethyl) sulfonyl] -4 ′-[2-[[(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] ethyl ] -4-Biphenylcarboxamide dihydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 1.30-2.01 (10H, m), 3.02-3.49 (6H, m), 3.67 (2H, t, J = 6.0Hz), 3.84 (2H, t, J = 5.8Hz), 4.75-4.89 (1H, m), 5.26-5.37 (1H, m), 7.32-7.45 (4H, m), 7.69-7.82 (3H, m), 7.97 (1H, d, J = 5.4 Hz), 8.5 (1H, d, J = 8.0Hz), 8.82-8.93 (2H, m), 9.31 (1H, br s), 9.43 (1H, br s), 11.1 (1H, br s)
(-) ESI-MS (m / z): 566 (MH) -

（７） Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エチル］−３−イソプロポキシ−４−ビフェニルカルボキサミド二塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.37 (6H, d, J=6Hz), 1.81-1.96 (2H, m), 3.03-3.6 (8H, m), 4.91-5.03 (1H, m), 5.25-5.34 (1H, m), 7.32-7.44 (4H, m), 7.68-7.77 (3H, m), 7.96 (1H, dd, J=5.6, 8Hz), 8.46 (1H, d, J=8Hz), 8.8-8.89 (2H, m), 9.26 (1H, br s), 9.37 (1H, br s), 11.22 (1H, s)
(-)ESI-MS (m/z): 540 (M-H)- (7) N-[(3-hydroxypropyl) sulfonyl] -4 ′-[2-[[(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] ethyl] -3-isopropoxy- 4-biphenylcarboxamide dihydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 1.37 (6H, d, J = 6Hz), 1.81-1.96 (2H, m), 3.03-3.6 (8H, m), 4.91-5.03 (1H, m) , 5.25-5.34 (1H, m), 7.32-7.44 (4H, m), 7.68-7.77 (3H, m), 7.96 (1H, dd, J = 5.6, 8Hz), 8.46 (1H, d, J = 8Hz ), 8.8-8.89 (2H, m), 9.26 (1H, br s), 9.37 (1H, br s), 11.22 (1H, s)
(-) ESI-MS (m / z): 540 (MH) -

（８） ３−（シクロヘキシルオキシ）−Ｎ−［（２−ヒドロキシエチル）スルホニル］−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エチル］−４−ビフェニルカルボキサミド塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.31-2.03 (10H, m), 3.00-3.29 (6H, m), 3.66 (2H, t, J=6Hz), 3.79-3.87 (2H, m), 4.76-4.87 (1H, m), 4.95-5.11 (2H, m), 6.23 (1H, d, J=3.6Hz), 7.31-7.44 (9H, m), 7.69-7.81 (3H, m)
(-)ESI-MS (m/z): 565 (M-H)- (8) 3- (Cyclohexyloxy) -N-[(2-hydroxyethyl) sulfonyl] -4 ′-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethyl] -4- Biphenyl carboxamide hydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 1.31-2.03 (10H, m), 3.00-3.29 (6H, m), 3.66 (2H, t, J = 6Hz), 3.79-3.87 (2H, m) , 4.76-4.87 (1H, m), 4.95-5.11 (2H, m), 6.23 (1H, d, J = 3.6Hz), 7.31-7.44 (9H, m), 7.69-7.81 (3H, m)
(-) ESI-MS (m / z): 565 (MH) -

製造例２
下記の化合物を実施例２と同様の方法にしたがって得た。
（１） ４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エチル］−３−（シクロヘプチルオキシ）−４−ビフェニルカルボン酸メチル
(+)ESI-MS (m/z): 589 (M+H)+ Production Example 2
The following compound was obtained according to the same method as in Example 2.
(1) 4 '-[2-[(Tertiary butoxycarbonyl) [(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] ethyl] -3- (cycloheptyloxy) -4- Methyl biphenylcarboxylate
(+) ESI-MS (m / z): 589 (M + H) +

（２） ４’−［３−［（第三級ブトキシカルボニル）［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］プロピル］−３−イソプロポキシ−４−ビフェニルカルボン酸メチル
(+)ESI-MS (m/z): 549 (M+H)+, 571 (M+Na)+ (2) 4 ′-[3-[(tertiary butoxycarbonyl) [(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] propyl] -3-isopropoxy-4-biphenylcarboxylic acid Methyl
(+) ESI-MS (m / z): 549 (M + H) + , 571 (M + Na) +

製造例３
４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エチル］−３−（シクロヘプチルオキシ）−４−ビフェニルカルボン酸メチル（８１３ｍｇ）のメタノール（８．１ｍｌ）とテトラヒドロフラン（２．４ｍｌ）中の溶液に、１Ｎ水酸化ナトリウム（４．１４ｍｌ）を加え、混合物を室温で２４時間攪拌した。１Ｎ塩酸（４．１４ｍｌ）を加えて混合物の反応を停止させ、溶媒を留去した。残留物をシリカゲルクロマトグラフィー（溶離溶媒：ヘキサン／酢酸エチル）に付して、４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エチル］−３−（シクロヘプチルオキシ）−４−ビフェニルカルボン酸（５７５ｍｇ）を白色固形物として得た。
(-)ESI-MS (m/z): 573 (M-H)- Production Example 3
4 ′-[2-[(Tertiary butoxycarbonyl) [(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] ethyl] -3- (cycloheptyloxy) -4-biphenylcarboxylic acid To a solution of methyl (813 mg) in methanol (8.1 ml) and tetrahydrofuran (2.4 ml) was added 1N sodium hydroxide (4.14 ml) and the mixture was stirred at room temperature for 24 hours. 1N hydrochloric acid (4.14 ml) was added to stop the reaction of the mixture, and the solvent was distilled off. The residue was subjected to silica gel chromatography (eluent: hexane / ethyl acetate) to give 4 ′-[2-[(tertiary butoxycarbonyl) [(2R) -2-hydroxy-2- (3-pyridyl)]. Ethyl] amino] ethyl] -3- (cycloheptyloxy) -4-biphenylcarboxylic acid (575 mg) was obtained as a white solid.
(-) ESI-MS (m / z): 573 (MH) -

製造例４
４−ブロモ−２−シクロペンチル安息香酸（４．０５ｇ）のＮ，Ｎ−ジメチルホルムアミド（４０ｍｌ）中の溶液に、Ｎ，Ｎ’−カルボニルジイミダゾール（２．６８ｇ）を室温で加え、混合物を４時間攪拌した。混合物に酢酸３−（アミノスルホニル）プロピル（３．０ｇ）と１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン（２．７ｍｌ）を加え、全体を１２０℃で２０時間攪拌した。室温まで冷却後、１Ｎ塩酸（１００ｍｌ）を加えて混合物の反応を停止させ、酢酸エチル（１００ｍｌ、５０ｍｌ）で抽出した。合わせた抽出物を水（１００ｍｌ×２）と食塩水（１００ｍｌ）で洗浄し、硫酸マグネシウムで乾燥した。濾過後、溶媒を留去して、黄色固形物（６．７７ｇ）を得て、これをシリカゲルクロマトグラフィー（溶離溶媒：ヘキサン／酢酸エチル）に付して、酢酸３−［［（４−ブロモ−２−シクロペンチルベンゾイル）アミノ］スルホニル］プロピル（５．２０ｇ）を白色固形物として得た。
(-)ESI-MS (m/z): 430, 432 (M-H)- Production Example 4
To a solution of 4-bromo-2-cyclopentylbenzoic acid (4.05 g) in N, N-dimethylformamide (40 ml) was added N, N′-carbonyldiimidazole (2.68 g) at room temperature and the mixture was converted to 4 Stir for hours. To the mixture were added 3- (aminosulfonyl) propyl acetate (3.0 g) and 1,8-diazabicyclo [5.4.0] undec-7-ene (2.7 ml), and the whole was stirred at 120 ° C. for 20 hours. . After cooling to room temperature, 1N hydrochloric acid (100 ml) was added to quench the mixture and extracted with ethyl acetate (100 ml, 50 ml). The combined extracts were washed with water (100 ml × 2) and brine (100 ml) and dried over magnesium sulfate. After filtration, the solvent was distilled off to obtain a yellow solid (6.77 g), which was subjected to silica gel chromatography (eluent: hexane / ethyl acetate) to give acetic acid 3-[[((4-bromo 2-Cyclopentylbenzoyl) amino] sulfonyl] propyl (5.20 g) was obtained as a white solid.
(-) ESI-MS (m / z): 430, 432 (MH) -

製造例５
酢酸３−［［（４−ブロモ−２−シクロペンチルベンゾイル）アミノ］スルホニル］プロピル（５．１７ｇ）、ビス（ピナコレート）ジボロン（３．３４ｇ）、［１，１’−ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）とジクロロメタンとの錯体（１：１、９７７ｍｇ）、１，１’−ビス（ジフェニルホスフィノ）フェロセン（３３１ｍｇ）、酢酸カリウム（４．７０ｇ）と１，４−ジオキサン（５２ｍｌ）の混合物を９５℃で２時間攪拌した。室温まで冷却後、０．５Ｎ塩酸（１００ｍｌ）を加えて混合物の反応を停止させ、酢酸エチル（１００ｍｌ）で抽出した。有機層を分離し、水（１００ｍｌ）と１０％塩化ナトリウム溶液（１００ｍｌ）で洗浄した。有機層に水（１００ｍｌ）、酢酸アンモニウム（４．１５ｇ）と過ヨウ素酸ナトリウム（８．９５ｇ）を加えた。混合物を室温で一夜攪拌した。不溶固形物を濾去し、酢酸エチルで洗浄し、有機層を分離した。有機層を０．５Ｎ塩酸（１００ｍｌ）と食塩水（１００ｍｌ）で洗浄し、硫酸マグネシウムで乾燥した。濾過後、溶媒を留去して、褐色固形物（６．６２ｇ）を得て、これをシリカゲルクロマトグラフィー（溶離溶媒：酢酸エチル／メタノール）に付して、［４−［［［［３−（アセチルオキシ）プロピル］スルホニル］アミノ］カルボニル］−３−シクロペンチルフェニル］ホウ素酸（３．３４ｇ）を褐色固形物として得た。
(-)ESI-MS (m/z): 396 (M-H)- Production Example 5
3-[[((4-Bromo-2-cyclopentylbenzoyl) amino] sulfonyl] propyl acetate (5.17 g), bis (pinacolato) diboron (3.34 g), [1,1′-bis (diphenylphosphino) ferrocene ] Complex of dichloropalladium (II) and dichloromethane (1: 1, 977 mg), 1,1'-bis (diphenylphosphino) ferrocene (331 mg), potassium acetate (4.70 g) and 1,4-dioxane (52 ml) ) Was stirred at 95 ° C. for 2 hours. After cooling to room temperature, 0.5N hydrochloric acid (100 ml) was added to quench the mixture, and the mixture was extracted with ethyl acetate (100 ml). The organic layer was separated and washed with water (100 ml) and 10% sodium chloride solution (100 ml). Water (100 ml), ammonium acetate (4.15 g) and sodium periodate (8.95 g) were added to the organic layer. The mixture was stirred overnight at room temperature. The insoluble solid was removed by filtration, washed with ethyl acetate, and the organic layer was separated. The organic layer was washed with 0.5N hydrochloric acid (100 ml) and brine (100 ml) and dried over magnesium sulfate. After filtration, the solvent was distilled off to obtain a brown solid (6.62 g), which was subjected to silica gel chromatography (elution solvent: ethyl acetate / methanol) to give [4-[[[[3- (Acetyloxy) propyl] sulfonyl] amino] carbonyl] -3-cyclopentylphenyl] boronic acid (3.34 g) was obtained as a brown solid.
(-) ESI-MS (m / z): 396 (MH) -

製造例６
［４−［［［［３−（アセチルオキシ）プロピル］スルホニル］アミノ］カルボニル］−３−シクロペンチルフェニル］ホウ素酸（３．２８ｇ）を２．５Ｎ塩化水素／メタノール（２０ｍｌ）に溶解し、混合物を室温で１７時間攪拌した。溶媒を留去して、［３−シクロペンチル−４−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］フェニル］ホウ素酸（３．１６ｇ）を褐色固形物として得た。
(-)ESI-MS (m/z): 354 (M-H)- Production Example 6
[4-[[[[3- (Acetyloxy) propyl] sulfonyl] amino] carbonyl] -3-cyclopentylphenyl] boronic acid (3.28 g) was dissolved in 2.5N hydrogen chloride / methanol (20 ml), and the mixture was dissolved. Was stirred at room temperature for 17 hours. The solvent was distilled off to give [3-cyclopentyl-4-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] phenyl] boronic acid (3.16 g) as a brown solid.
(-) ESI-MS (m / z): 354 (MH) -

製造例７
２−ブロモエタノール（７．０ｇ）とチオシアン酸カリウム（５．４ｇ）のメタノール（４０ｍｌ）中の混合物を７時間還流した。沈殿物を濾去後、濾液から溶媒を減圧留去した。残留物をクロロホルム／メタノール（５／１）に懸濁した。沈殿物を濾去した。濾液から溶媒を減圧留去して、チオシアン酸塩（４．４ｇ）を得た。チオシアン酸塩のピリジン（４．８ｍｌ）／ジクロロメタン（２０ｍｌ）中の混合物に、ジクロロメタン（５ｍｌ）中の無水酢酸（５．３ｍｌ）を５℃で加えた。混合物を室温で６時間攪拌した。沈殿物を濾去した。濾液を水で洗浄し、硫酸ナトリウムで乾燥後、溶媒を減圧留去して、酢酸２−チオシアネートエチル（５．６ｇ）を得た。
NMR (200 MHz, DMSO-d6, δ): 2.06 (3H, s), 3.36 (2H, t, J=5.8Hz), 4.32 (2H, t, J=5.8Hz) Production Example 7
A mixture of 2-bromoethanol (7.0 g) and potassium thiocyanate (5.4 g) in methanol (40 ml) was refluxed for 7 hours. After removing the precipitate by filtration, the solvent was distilled off from the filtrate under reduced pressure. The residue was suspended in chloroform / methanol (5/1). The precipitate was removed by filtration. The solvent was distilled off from the filtrate under reduced pressure to obtain thiocyanate (4.4 g). To a mixture of thiocyanate in pyridine (4.8 ml) / dichloromethane (20 ml) was added acetic anhydride (5.3 ml) in dichloromethane (5 ml) at 5 ° C. The mixture was stirred at room temperature for 6 hours. The precipitate was removed by filtration. The filtrate was washed with water and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain ethyl acetate 2-thiocyanate (5.6 g).
NMR (200 MHz, DMSO-d 6 , δ): 2.06 (3H, s), 3.36 (2H, t, J = 5.8Hz), 4.32 (2H, t, J = 5.8Hz)

製造例８
酢酸２−チオシアネートエチル（５．６ｇ）の水（２０ｍｌ）中の溶液に、氷冷下に攪拌しながら塩素ガスを２０分間吹き込み、ジクロロメタンで抽出した。抽出物を硫酸ナトリウムで乾燥後、溶媒を減圧留去して、塩化スルホニル（６．０ｇ、無色油状物）を得た。塩化スルホニルをジクロロメタン（６０ｍｌ）に溶解し、アンモニアガスを氷冷下に１時間吹き込んだ。沈殿物を濾去し、濾液を水で洗浄し、硫酸ナトリウムで乾燥後、溶媒を減圧留去した。残留物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝９２／８〜９０／１０）で精製して、酢酸２−（アミノスルホニル）エチル（３８５ｍｇ）を得た。
NMR (200 MHz, CDCl3, δ): 2.11 (3H, s), 3.47 (2H, t, J=6.0Hz), 4.54 (2H, t, J=6.0Hz), 5.10 (2H, br s)
(-)ESI-MS (m/z): 166 (M-H)- Production Example 8
Chlorine gas was blown into a solution of ethyl 2-thiocyanate acetate (5.6 g) in water (20 ml) with stirring under ice-cooling for 20 minutes and extracted with dichloromethane. The extract was dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give sulfonyl chloride (6.0 g, colorless oil). The sulfonyl chloride was dissolved in dichloromethane (60 ml), and ammonia gas was blown for 1 hour under ice cooling. The precipitate was removed by filtration, the filtrate was washed with water and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 92/8 to 90/10) to obtain 2- (aminosulfonyl) ethyl acetate (385 mg).
NMR (200 MHz, CDCl 3 , δ): 2.11 (3H, s), 3.47 (2H, t, J = 6.0Hz), 4.54 (2H, t, J = 6.0Hz), 5.10 (2H, br s)
(-) ESI-MS (m / z): 166 (MH) -

製造例９
［（２−ブロモエトキシ）メチル］ベンゼン（６．０ｇ）と硫酸ナトリウム（３．９ｇ）の水（１２ｍｌ）とエタノール（３６ｍｌ）中の混合物を一夜還流した。混合物を氷冷下に濃塩酸で酸性にした。混合物から溶媒を減圧留去した。残留物をジクロロメタン／メタノール（４／１）に懸濁し、セライトパッドで濾去した。濾液から溶媒を留去して、２−（ベンジルオキシ）エタンスルホン酸（４．５ｇ）を得た。
(-)ESI-MS (m/z): 215 (M-H)- Production Example 9
A mixture of [(2-bromoethoxy) methyl] benzene (6.0 g) and sodium sulfate (3.9 g) in water (12 ml) and ethanol (36 ml) was refluxed overnight. The mixture was acidified with concentrated hydrochloric acid under ice cooling. The solvent was distilled off from the mixture under reduced pressure. The residue was suspended in dichloromethane / methanol (4/1) and filtered off through a celite pad. The solvent was distilled off from the filtrate to obtain 2- (benzyloxy) ethanesulfonic acid (4.5 g).
(-) ESI-MS (m / z): 215 (MH) -

製造例１０
２−（ベンジルオキシ）エタンスルホン酸（４．０ｇ）に塩化チオニル（１３．５ｍｌ）を室温で１５分間かけて滴下し、混合物を同温で１０分間攪拌した。混合物にＮ，Ｎ−ジメチルホルムアミド（０．０７２ｍｌ）を室温で滴下した。混合物を同温で２０分間攪拌し、１時間還流した。室温まで冷却後、混合物から溶媒を減圧留去して、塩化２−（ベンジルオキシ）エタンスルホニル（４．１ｇ）を得た。
NMR (200 MHz, CDCl3, δ): 3.92-4.08 (4H, m), 4.60 (2H, s), 7.32-7.39 (5H, m) Production Example 10
To 2- (benzyloxy) ethanesulfonic acid (4.0 g), thionyl chloride (13.5 ml) was added dropwise at room temperature over 15 minutes, and the mixture was stirred at the same temperature for 10 minutes. N, N-dimethylformamide (0.072 ml) was added dropwise to the mixture at room temperature. The mixture was stirred at the same temperature for 20 minutes and refluxed for 1 hour. After cooling to room temperature, the solvent was distilled off from the mixture under reduced pressure to obtain 2- (benzyloxy) ethanesulfonyl chloride (4.1 g).
NMR (200 MHz, CDCl 3 , δ): 3.92-4.08 (4H, m), 4.60 (2H, s), 7.32-7.39 (5H, m)

製造例１１
２８％水酸化アンモニウム（１０ｍｌ）に、ジクロロメタン（１０ｍｌ）中の塩化２−（ベンジルオキシ）エタンスルホニル（４．１ｇ）を氷冷下に１０分間かけて滴下した。混合物を室温で一夜攪拌した。有機層を分離し、水層をジクロロメタン／メタノール（５／１）で抽出した。合わせた有機層を硫酸ナトリウムで乾燥後、溶媒を減圧留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝５０／５０）で精製して、２−（ベンジルオキシ）エタンスルホンアミド（１．６ｇ）を得た。
NMR (200 MHz, CDCl3, δ): 3.39 (2H, t, J=5.5Hz), 3.96 (2H, t, J=5.5Hz), 4.57 (2H, s), 4.84 (2H, br s), 7.30-7.42 (5H, m)
(+)ESI-MS (m/z): 238 (M+Na)+ Production Example 11
To 28% ammonium hydroxide (10 ml), 2- (benzyloxy) ethanesulfonyl chloride (4.1 g) in dichloromethane (10 ml) was added dropwise over 10 minutes under ice cooling. The mixture was stirred overnight at room temperature. The organic layer was separated and the aqueous layer was extracted with dichloromethane / methanol (5/1). The combined organic layers were dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 50/50) to give 2- (benzyloxy) ethanesulfonamide (1.6 g).
NMR (200 MHz, CDCl 3 , δ): 3.39 (2H, t, J = 5.5Hz), 3.96 (2H, t, J = 5.5Hz), 4.57 (2H, s), 4.84 (2H, br s), 7.30-7.42 (5H, m)
(+) ESI-MS (m / z): 238 (M + Na) +

製造例１２
下記の化合物を製造例４と同様の方法にしたがって得た。
（１） 酢酸３−［［［４−ブロモ−２−（シクロヘキシルオキシ）ベンゾイル］アミノ］スルホニル］プロピル
(-)ESI-MS (m/z): 460 (M-H)- Production Example 12
The following compound was obtained according to the same method as in Production Example 4.
(1) 3-[[[[4-Bromo-2- (cyclohexyloxy) benzoyl] amino] sulfonyl] propyl acetate
(-) ESI-MS (m / z): 460 (MH) -

（２） Ｎ−［［２−（ベンジルオキシ）エチル］スルホニル］−４−ブロモ−２−（シクロヘキシルオキシ）ベンズアミド
(-)ESI-MS (m/z): 494 (M-H)- (2) N-[[2- (Benzyloxy) ethyl] sulfonyl] -4-bromo-2- (cyclohexyloxy) benzamide
(-) ESI-MS (m / z): 494 (MH) -

（３） 酢酸３−［［（４−ブロモ−２−イソプロポキシベンゾイル）アミノ］スルホニル］プロピル
(+)ESI-MS (m/z): 444 (M+Na)+ (3) 3-[[[(4-Bromo-2-isopropoxybenzoyl) amino] sulfonyl] propyl acetate
(+) ESI-MS (m / z): 444 (M + Na) +

製造例１３
下記の化合物を製造例５と同様の方法にしたがって得た。
（１） ［４−［［［［３−（アセチルオキシ）プロピル］スルホニル］アミノ］カルボニル］−３−（シクロヘキシルオキシ）フェニル］ホウ素酸
(+)ESI-MS (m/z): 450 (M+Na)+ Production Example 13
The following compound was obtained according to the same method as in Production Example 5.
(1) [4-[[[[[3- (Acetyloxy) propyl] sulfonyl] amino] carbonyl] -3- (cyclohexyloxy) phenyl] boronic acid
(+) ESI-MS (m / z): 450 (M + Na) +

（２） ［４−［［［２−（ベンジルオキシ）エチル］スルホニル］アミノ］カルボニル］−３−（シクロヘキシルオキシ）フェニル］ホウ素酸
(+)ESI-MS (m/z): 484 (M+Na)+ (2) [4-[[[2- (Benzyloxy) ethyl] sulfonyl] amino] carbonyl] -3- (cyclohexyloxy) phenyl] boronic acid
(+) ESI-MS (m / z): 484 (M + Na) +

（３） ［４−［［［［３−（アセチルオキシ）プロピル］スルホニル］アミノ］カルボニル］−３−イソプロポキシフェニル］ホウ素酸
(+)ESI-MS (m/z): 410 (M+Na)+ (3) [4-[[[[[3- (Acetyloxy) propyl] sulfonyl] amino] carbonyl] -3-isopropoxyphenyl] boronic acid
(+) ESI-MS (m / z): 410 (M + Na) +

（４） ［４−［［［［３−（アセチルオキシ）プロピル］スルホニル］アミノ］カルボニル］−３−イソブチルフェニル］ホウ素酸
(-)ESI-MS (m/z): 384 (M-H)- (4) [4-[[[[[3- (Acetyloxy) propyl] sulfonyl] amino] carbonyl] -3-isobutylphenyl] boronic acid
(-) ESI-MS (m / z): 384 (MH) -

製造例１４
下記の化合物を製造例６と同様の方法にしたがって得た。
（１） ［３−（シクロヘキシルオキシ）−４−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］フェニル］ホウ素酸
(+)ESI-MS (m/z): 450 (M+Na)+ Production Example 14
The following compound was obtained according to the same method as in Production Example 6.
(1) [3- (Cyclohexyloxy) -4-[[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] phenyl] boronic acid
(+) ESI-MS (m / z): 450 (M + Na) +

（２） ［４−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−３−イソプロポキシフェニル］ホウ素酸
(+)ESI-MS (m/z): 368 (M+Na)+ (2) [4-[[[[(3-Hydroxypropyl) sulfonyl] amino] carbonyl] -3-isopropoxyphenyl] boronic acid
(+) ESI-MS (m / z): 368 (M + Na) +

（３） ［４−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−３−イソブチルフェニル］ホウ素酸
(-)ESI-MS (m/z): 342 (M-H)- (3) [4-[[[[(3-Hydroxypropyl) sulfonyl] amino] carbonyl] -3-isobutylphenyl] boronic acid
(-) ESI-MS (m / z): 342 (MH) -

製造例１５
下記の化合物を実施例１５と同様の方法にしたがって得た。
（１） ４’−［２−［（第三級ブトキシカルボニル）［（１Ｓ，２Ｒ）−２−ヒドロキシ−１−メチル−２−フェニルエチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニルカルボン酸メチル
(+)ESI-MS (m/z): 610 (M+Na)+ Production Example 15
The following compound was obtained according to the same method as in Example 15.
(1) 4 '-[2-[(Tertiary butoxycarbonyl) [(1S, 2R) -2-hydroxy-1-methyl-2-phenylethyl] amino] ethyl] -3- (cyclohexyloxy) -4 -Methyl biphenylcarboxylate
(+) ESI-MS (m / z): 610 (M + Na) +

（２） ４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−フェニル−２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エチル］アミノ］エチル］−３−シクロペンチル−４−ビフェニルカルボン酸メチル
(+)ESI-MS (m/z): 650 (M+Na)+ (2) 4 ′-[2-[(Tertiary butoxycarbonyl) [(2R) -2-phenyl-2- (tetrahydro-2H-pyran-2-yloxy) ethyl] amino] ethyl] -3-cyclopentyl- Methyl 4-biphenylcarboxylate
(+) ESI-MS (m / z): 650 (M + Na) +

（３） ［２−［４’−（アミノスルホニル）−３’−（シクロヘキシルオキシ）−４−ビフェニリル］エチル］［（２Ｒ）−２−フェニル−２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エチル］カルバミン第三級ブチル
(+)ESI-MS (m/z): 701 (M+Na)+ (3) [2- [4 ′-(Aminosulfonyl) -3 ′-(cyclohexyloxy) -4-biphenylyl] ethyl] [(2R) -2-phenyl-2- (tetrahydro-2H-pyran-2-yloxy) ) Ethyl] carbamine tertiary butyl
(+) ESI-MS (m / z): 701 (M + Na) +

製造例１６
下記の化合物を製造例３と同様の方法にしたがって得た。
（１） ４’−［２−［（第三級ブトキシカルボニル）［（１Ｓ，２Ｒ）−２−ヒドロキシ−１−メチル−２−フェニルエチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニルカルボン酸
(+)ESI-MS (m/z): 610 (M+Na)+ Production Example 16
The following compound was obtained according to the same method as in Production Example 3.
(1) 4 '-[2-[(Tertiary butoxycarbonyl) [(1S, 2R) -2-hydroxy-1-methyl-2-phenylethyl] amino] ethyl] -3- (cyclohexyloxy) -4 -Biphenylcarboxylic acid
(+) ESI-MS (m / z): 610 (M + Na) +

（２） ４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−フェニル−２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エチル］アミノ］エチル］−３−シクロペンチル−４−ビフェニルカルボン酸
(-)ESI-MS (m/z): 612 (M-H)- (2) 4 ′-[2-[(Tertiary butoxycarbonyl) [(2R) -2-phenyl-2- (tetrahydro-2H-pyran-2-yloxy) ethyl] amino] ethyl] -3-cyclopentyl- 4-biphenylcarboxylic acid
(-) ESI-MS (m / z): 612 (MH) -

（３） ４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］−３−（イソプロピルチオ）−４−ビフェニルカルボン酸
(-)ESI-MS (m/z): 568, 570 (M-H)- (3) 4 ′-[2-[(Tertiary butoxycarbonyl) [(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] -3- (isopropylthio) -4-biphenyl carboxylic acid
(-) ESI-MS (m / z): 568, 570 (MH) -

（４） ４’−［３−［（第三級ブトキシカルボニル）［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］プロピル］−３−イソプロポキシ−４−ビフェニルカルボン酸
(-)ESI-MS (m/z): 533 (M-H)- (4) 4 ′-[3-[(tertiary butoxycarbonyl) [(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] propyl] -3-isopropoxy-4-biphenylcarboxylic acid
(-) ESI-MS (m / z): 533 (MH) -

製造例１７
下記の化合物を実施例２６と同様の方法にしたがって得た。 Production Example 17
The following compound was obtained in the same manner as in Example 26.

４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］−３−（イソプロピルチオ）−４−ビフェニルカルボン酸メチル
(+)ESI-MS (m/z): 606 (M+Na)+ 4 ′-[2-[(Tertiary butoxycarbonyl) [(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] -3- (isopropylthio) -4-biphenylcarboxylate methyl ester
(+) ESI-MS (m / z): 606 (M + Na) +

製造例１８
下記の化合物を実施例１１と同様の方法にしたがって得た。 Production Example 18
The following compound was obtained according to the same method as in Example 11.

酢酸３−［［（４−ブロモ−２−イソブチルベンゾイル）アミノ］スルホニル］プロピル
(-)ESI-MS (m/z): 418, 420 (M-H)- 3-[[((4-Bromo-2-isobutylbenzoyl) amino] sulfonyl] propyl acetate
(-) ESI-MS (m / z): 418, 420 (MH) -

製造例１９
下記の化合物を製造例７と同様の方法にしたがって得た。
（１） ３−チオシアネートプロパン酸メチル
(+)ESI-MS (m/z): 168 (M+Na)+ Production Example 19
The following compound was obtained according to the same method as in Production Example 7.
(1) Methyl 3-thiocyanate propanoate
(+) ESI-MS (m / z): 168 (M + Na) +

（２） チオシアン酸４−ヒドロキシブチル
NMR (200 MHz, CDCl3, δ): 1.69-1.79 (2H, m), 1.9-2.03 (2H, m), 2.99-3.06 (2H, m), 3.68-3.74 (2H, m), 4.00 (1H, s) (2) 4-hydroxybutyl thiocyanate
NMR (200 MHz, CDCl 3 , δ): 1.69-1.79 (2H, m), 1.9-2.03 (2H, m), 2.99-3.06 (2H, m), 3.68-3.74 (2H, m), 4.00 (1H , s)

（３） 酢酸４−チオシアネートブチル
NMR (200 MHz, CDCl3, δ): 1.77-2.07 (4H, m), 2.10 (3H, s), 2.99 (2H, t, J=7Hz), 4.12 (2H, t, J=6.1Hz) (3) 4-thiocyanate butyl acetate
NMR (200 MHz, CDCl 3 , δ): 1.77-2.07 (4H, m), 2.10 (3H, s), 2.99 (2H, t, J = 7Hz), 4.12 (2H, t, J = 6.1Hz)

製造例２０
３−チオシアネートプロパン酸メチル（２．００ｇ）を水（２０ｍｌ）に溶解し、０℃に冷却した。塩素ガスを溶液に同温で１時間吹き込んだ。反応混合物を冷水とジエチルエーテルの混合物に注ぎ、水層を分離した。有機層を食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を留去して、３−（クロロスルホニル）プロパン酸メチル（２．３１ｇ）を得た。
NMR (200 MHz, CDCl3, δ): 3.06 (2H, t, J=8Hz), 3.79 (3H, s), 4.01 (2H, d, J=8Hz) Production Example 20
Methyl 3-thiocyanate propanoate (2.00 g) was dissolved in water (20 ml) and cooled to 0 ° C. Chlorine gas was blown into the solution at the same temperature for 1 hour. The reaction mixture was poured into a mixture of cold water and diethyl ether, and the aqueous layer was separated. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off to obtain methyl 3- (chlorosulfonyl) propanoate (2.31 g).
NMR (200 MHz, CDCl 3 , δ): 3.06 (2H, t, J = 8Hz), 3.79 (3H, s), 4.01 (2H, d, J = 8Hz)

製造例２１
３−（クロロスルホニル）プロパン酸メチル（２．３１ｇ）をジクロロメタン（１．８５ｍｌ）とテトラヒドロフラン（４．６０ｍｌ）に溶解し、−１０℃に冷却した。アンモニアガスを溶液に同温で１．５時間吹き込んだ。セライトで濾過後、反応混合物から溶媒を留去した。残留物を、クロロホルムとメタノールを溶離溶媒として用いるシリカゲルカラムクロマトグラフィーで精製して、３−（アミノスルホニル）プロパン酸メチル（１．８０ｇ）を得た。
NMR (400 MHz, CDCl3, δ): 2.90 (2H, t, J=7.2Hz), 3.48 (2H, t, J=7.2Hz), 3.74 (3H, s), 4.94 (2H, br s)
(+)ESI-MS (m/z): 190 (M+Na)+ Production Example 21
Methyl 3- (chlorosulfonyl) propanoate (2.31 g) was dissolved in dichloromethane (1.85 ml) and tetrahydrofuran (4.60 ml) and cooled to -10 ° C. Ammonia gas was bubbled through the solution at the same temperature for 1.5 hours. After filtration through celite, the solvent was distilled off from the reaction mixture. The residue was purified by silica gel column chromatography using chloroform and methanol as eluents to give methyl 3- (aminosulfonyl) propanoate (1.80 g).
NMR (400 MHz, CDCl 3 , δ): 2.90 (2H, t, J = 7.2Hz), 3.48 (2H, t, J = 7.2Hz), 3.74 (3H, s), 4.94 (2H, br s)
(+) ESI-MS (m / z): 190 (M + Na) +

製造例２２
下記の化合物を製造例２０と同様の方法にしたがって得た。 Production Example 22
The following compound was obtained according to the same method as in Production Example 20.

酢酸４−（クロロスルホニル）ブチル
NMR (200 MHz, CDCl3, δ): 1.79-1.93 (2H, m), 2.07 (3H, s), 2.07-2.23 (2H, m), 3.72 (2H, t, J=7.7Hz), 4.14 (2H, t, J=6.1Hz) 4- (Chlorosulfonyl) butyl acetate
NMR (200 MHz, CDCl 3 , δ): 1.79-1.93 (2H, m), 2.07 (3H, s), 2.07-2.23 (2H, m), 3.72 (2H, t, J = 7.7Hz), 4.14 ( (2H, t, J = 6.1Hz)

製造例２３
下記の化合物を製造例２１と同様の方法にしたがって得た。 Production Example 23
The following compound was obtained according to the same method as in Production Example 21.

酢酸４−（アミノスルホニル）ブチル
(-)ESI-MS (m/z): 194 (M-H)- 4- (Aminosulfonyl) butyl acetate
(-) ESI-MS (m / z): 194 (MH) -

製造例２４
水酸化アンモニウム（２８％、８０ｍｌ）に、塩化４−ブロモ−２−フルオロベンゼンスルホニル（１０ｇ）のジクロロメタン（８０ｍｌ）中の溶液を約０℃で１時間かけて滴下した。反応混合物を同温でさらに２時間激しく攪拌した。層を分離した。水相をジクロロメタンで洗浄した。合わせた有機抽出物を食塩水で洗浄し、硫酸ナトリウムで乾燥後、溶媒を留去して、４−ブロモ−２−フルオロベンゼンスルホンアミド（８．０ｇ）を得た。
(+)ESI-MS (m/z): 276 (M+Na)+ Production Example 24
To ammonium hydroxide (28%, 80 ml), a solution of 4-bromo-2-fluorobenzenesulfonyl chloride (10 g) in dichloromethane (80 ml) was added dropwise at about 0 ° C. over 1 hour. The reaction mixture was stirred vigorously at the same temperature for another 2 hours. The layers were separated. The aqueous phase was washed with dichloromethane. The combined organic extracts were washed with brine, dried over sodium sulfate, and the solvent was evaporated to give 4-bromo-2-fluorobenzenesulfonamide (8.0 g).
(+) ESI-MS (m / z): 276 (M + Na) +

製造例２５
水素化ナトリウム（６０％、０．６５ｇ）のＮ，Ｎ−ジメチルホルムアミド（２２ｍｌ）中の懸濁液に、シクロヘキサノール（２．７ｍｌ）のＮ，Ｎ−ジメチルホルムアミド（６ｍｌ）中の溶液を室温で３０分間かけて加えた。懸濁液を室温で３０分間攪拌した。４−ブロモ−２−フルオロベンゼンスルホンアミド（３ｇ）のＮ，Ｎ−ジメチルホルムアミド（１３ｍｌ）中の溶液を室温で３０分間かけて滴下した。懸濁液を室温で１時間、６０℃で２時間攪拌した。懸濁液を氷（３５ｍｌ）と塩酸水溶液（１Ｎ、３５ｍｌ）の混合物に注ぎ、混合物を室温で１時間攪拌した。混合物を濾過して沈殿物を採取し、沈殿物を水とヘキサンで洗浄した。沈殿物を減圧乾燥して、４−ブロモ−２−（シクロヘキシルオキシ）ベンゼンスルホンアミド（３．６ｇ）を得た。
(+)ESI-MS (m/z): 356 (M+Na)+ Production Example 25
To a suspension of sodium hydride (60%, 0.65 g) in N, N-dimethylformamide (22 ml) was added a solution of cyclohexanol (2.7 ml) in N, N-dimethylformamide (6 ml) at room temperature. Over 30 minutes. The suspension was stirred at room temperature for 30 minutes. A solution of 4-bromo-2-fluorobenzenesulfonamide (3 g) in N, N-dimethylformamide (13 ml) was added dropwise at room temperature over 30 minutes. The suspension was stirred at room temperature for 1 hour and at 60 ° C. for 2 hours. The suspension was poured into a mixture of ice (35 ml) and aqueous hydrochloric acid (1N, 35 ml) and the mixture was stirred at room temperature for 1 hour. The mixture was filtered to collect the precipitate, and the precipitate was washed with water and hexane. The precipitate was dried under reduced pressure to obtain 4-bromo-2- (cyclohexyloxy) benzenesulfonamide (3.6 g).
(+) ESI-MS (m / z): 356 (M + Na) +

製造例２６
４−ブロモ−２−（シクロヘキシルオキシ）ベンゼンスルホンアミド（３．６ｇ）の１，４−ジオキサン（３５ｍｌ）中の溶液に、ビス（ピナコレート）ジボロン（３．０ｇ）、ジクロロビス（トリフェニルホスフィン）パラジウム（ＩＩ）（５２８ｍｇ）と酢酸カリウム（３．１６ｇ）を加え、混合物を窒素雰囲気下に９５℃で２時間攪拌した。室温まで冷却後、混合物を食塩水に注ぎ、酢酸エチルで抽出した。有機層を分離し、食塩水で洗浄し、硫酸ナトリウムで乾燥後、溶媒を減圧留去して、残留物（６．４ｇ）を得た。上記の残留物の酢酸エチル（５０ｍｌ）と水（５０ｍｌ）中の混合物に、酢酸アンモニウム（１．８ｇ）と過ヨウ素酸ナトリウム（５．０ｇ）を加えた。混合物を室温で一夜攪拌した。沈殿物を濾去し、沈殿物を酢酸エチル／メタノール（９／１）で洗浄した。濾液を塩酸水溶液（０．５Ｎ）と食塩水で洗浄し、硫酸ナトリウムで乾燥後、溶媒を減圧留去した。残留物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝９５／５）で精製して、［４−（アミノスルホニル）−３−（シクロヘキシルオキシ）フェニル］ホウ素酸（２．５ｇ）を得た。
(+)ESI-MS (m/z): 322 (M+Na)+ Production Example 26
To a solution of 4-bromo-2- (cyclohexyloxy) benzenesulfonamide (3.6 g) in 1,4-dioxane (35 ml) was added bis (pinacolato) diboron (3.0 g), dichlorobis (triphenylphosphine) palladium. (II) (528 mg) and potassium acetate (3.16 g) were added, and the mixture was stirred at 95 ° C. for 2 hours under a nitrogen atmosphere. After cooling to room temperature, the mixture was poured into brine and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a residue (6.4 g). To a mixture of the above residue in ethyl acetate (50 ml) and water (50 ml) was added ammonium acetate (1.8 g) and sodium periodate (5.0 g). The mixture was stirred overnight at room temperature. The precipitate was filtered off and the precipitate was washed with ethyl acetate / methanol (9/1). The filtrate was washed with aqueous hydrochloric acid (0.5N) and brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 95/5) to obtain [4- (aminosulfonyl) -3- (cyclohexyloxy) phenyl] boronic acid (2.5 g).
(+) ESI-MS (m / z): 322 (M + Na) +

実施例２
［２−（４−ブロモフェニル）エチル］［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］カルバミン酸第三級ブチル（２５０ｍｇ）、［４−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−３−イソプロポキシフェニル］ホウ素酸（２２８ｍｇ）、［１，１’−ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（ＩＩ）とジクロロメタンとの錯体（１：１、６７．３ｍｇ）、１，１’−ビス（ジフェニルホスフィノ）フェロセン（４５．７ｍｇ）、Ｎ，Ｎ−ジメチルホルムアミド（５ｍｌ）と２Ｎ炭酸ナトリウム溶液（１．３２ｍｌ）の混合物を８０℃で２時間攪拌した。室温まで冷却後、１Ｎ塩酸（２．６４ｍｌ）を加えて混合物の反応を停止させ、酢酸エチル（２０ｍｌ）と水（２０ｍｌ）との間に分配した。有機層を分離し、水（２０ｍｌ×２）と食塩水（２０ｍｌ）で洗浄し、硫酸マグネシウムで乾燥した。濾過後、溶媒を留去して、褐色泡状物を得て、これをシリカゲルクロマトグラフィー（溶離溶媒：ヘキサン／酢酸エチル）に付して、［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］［２−［４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−３’−イソプロポキシ−４−ビフェニリル］エチル］カルバミン酸第三級ブチル（２３６ｍｇ）を淡黄色固形物として得た。
(-)ESI-MS (m/z): 673 (M-H)- Example 2
[2- (4-Bromophenyl) ethyl] [(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] tertiary butyl carbamate (250 mg), [4-[[[(3-hydroxypropyl ) Sulfonyl] amino] carbonyl] -3-isopropoxyphenyl] boronic acid (228 mg), [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (II) and dichloromethane complex (1: 1, 67 .3 mg), 1,1′-bis (diphenylphosphino) ferrocene (45.7 mg), N, N-dimethylformamide (5 ml) and 2N sodium carbonate solution (1.32 ml) were stirred at 80 ° C. for 2 hours. did. After cooling to room temperature, 1N hydrochloric acid (2.64 ml) was added to quench the mixture and partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was separated, washed with water (20 ml × 2) and brine (20 ml), and dried over magnesium sulfate. After filtration, the solvent was distilled off to give a brown foam which was subjected to silica gel chromatography (eluent: hexane / ethyl acetate) to give [(2R) -2- (3-chlorophenyl)- 2-hydroxyethyl] [2- [4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -3′-isopropoxy-4-biphenylyl] ethyl] tertiary butyl carbamate (236 mg). Obtained as a pale yellow solid.
(-) ESI-MS (m / z): 673 (MH) -

実施例３
［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］［２−［４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−３’−イソプロポキシ−４−ビフェニリル］エチル］カルバミン酸第三級ブチル（２３１ｍｇ）の１，４−ジオキサン（２．３ｍｌ）中の溶液に、４Ｎ塩化水素／１，４−ジオキサン（２．３ｍｌ）を加え、混合物を室温で５時間攪拌した。沈殿物を濾取し、１，４−ジオキサンで洗浄し、減圧乾燥して、４’−［２−［［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−３−イソプロポキシ−４−ビフェニルカルボキサミド塩酸塩（１５８ｍｇ）を白色固形物として得た。
NMR (400 MHz, DMSO-d6, δ): 1.33 (6H, d, J=6.2Hz), 1.85-1.92 (2H, m), 3.01-3.12 (3H, m), 3.19-3.27 (3H, m), 3.49-3.55 (4H, m), 4.74 (1H, t, J=5.1Hz), 4.92-5.04 (2H, m), 6.37 (1H, d, J=4.0Hz), 7.34-7.49 (8H, m), 7.70 (1H, d, J=8.1Hz), 7.74 (2H, d, J=8.4Hz), 9.06 (2H, br), 11.2 (1H, br)
(-)ESI-MS (m/z): 573 (M-H)- Example 3
[(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] [2- [4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -3′-isopropoxy-4-biphenylyl ] To a solution of tertiary butyl carbamate (231 mg) in 1,4-dioxane (2.3 ml) was added 4N hydrogen chloride / 1,4-dioxane (2.3 ml) and the mixture was stirred at room temperature for 5 minutes. Stir for hours. The precipitate was collected by filtration, washed with 1,4-dioxane, dried under reduced pressure, and 4 ′-[2-[[(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl]. -N-[(3-hydroxypropyl) sulfonyl] -3-isopropoxy-4-biphenylcarboxamide hydrochloride (158 mg) was obtained as a white solid.
NMR (400 MHz, DMSO-d 6 , δ): 1.33 (6H, d, J = 6.2Hz), 1.85-1.92 (2H, m), 3.01-3.12 (3H, m), 3.19-3.27 (3H, m ), 3.49-3.55 (4H, m), 4.74 (1H, t, J = 5.1Hz), 4.92-5.04 (2H, m), 6.37 (1H, d, J = 4.0Hz), 7.34-7.49 (8H, m), 7.70 (1H, d, J = 8.1Hz), 7.74 (2H, d, J = 8.4Hz), 9.06 (2H, br), 11.2 (1H, br)
(-) ESI-MS (m / z): 573 (MH) -

実施例４
下記の化合物を実施例２と同様の方法にしたがって得た。
（１） ［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］［２−［［４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−３’−イソプロポキシ−４−ビフェニリル］オキシ］エチル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 655 (M-H)- Example 4
The following compound was obtained according to the same method as in Example 2.
(1) [(2R) -2-hydroxy-2-phenylethyl] [2-[[4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -3′-isopropoxy-4-biphenylyl ] Oxy] ethyl] tertiary butyl carbamate
(-) ESI-MS (m / z): 655 (MH) -

（２） ［２−［［３’−（シクロヘキシルオキシ）−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］オキシ］エチル］［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 695 (M-H)- (2) [2-[[3 ′-(Cyclohexyloxy) -4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -4-biphenylyl] oxy] ethyl] [(2R) -2- Hydroxy-2-phenylethyl] tertiary butyl carbamate
(-) ESI-MS (m / z): 695 (MH) -

（３） ［２−［［３’−シクロペンチル−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］オキシ］エチル］［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 665 (M-H)- (3) [2-[[3′-Cyclopentyl-4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -4-biphenylyl] oxy] ethyl] [(2R) -2-hydroxy-2 -Phenylethyl] tertiary butyl carbamate
(-) ESI-MS (m / z): 665 (MH) -

（４） ［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］［２−［［４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−３’−イソプロポキシ−４−ビフェニリル］オキシ］エチル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 689 (M-H)- (4) [(2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] [2-[[4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -3′-isopropoxy -4-biphenylyl] oxy] ethyl] tertiary butyl carbamate
(-) ESI-MS (m / z): 689 (MH) -

（５） ［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］［２−［［３’−シクロペンチル−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］オキシ］エチル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 699 (M-H)- (5) [(2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] [2-[[3′-cyclopentyl-4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl]- 4-Biphenylyl] oxy] ethyl] tertiary butyl carbamate
(-) ESI-MS (m / z): 699 (MH) -

（６） 酢酸３−［［［［４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（６−クロロ−３−ピリジル）−２−ヒドロキシエチル］アミノ］エトキシ］−３−（シクロヘキシルオキシ）−４−ビフェニリル］カルボニル］アミノ］スルホニル］プロピル
(-)ESI-MS (m/z): 772 (M-H)- (6) Acetic acid 3-[[[[4 '-[2-[(tertiary butoxycarbonyl) [(2R) -2- (6-chloro-3-pyridyl) -2-hydroxyethyl] amino] ethoxy] -3- (cyclohexyloxy) -4-biphenylyl] carbonyl] amino] sulfonyl] propyl
(-) ESI-MS (m / z): 772 (MH) -

（７） ［２−［３’−（シクロヘキシルオキシ）−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］エチル］［（２Ｒ）−２−ヒドロキシ−２−（４−ニトロフェニル）エチル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 724 (M-H)- (7) [2- [3 ′-(Cyclohexyloxy) -4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -4-biphenylyl] ethyl] [(2R) -2-hydroxy-2 -(4-Nitrophenyl) ethyl] tertiary butyl carbamate
(-) ESI-MS (m / z): 724 (MH) -

（８） ［（２Ｒ）−２−ヒドロキシ−２−（４−ニトロフェニル）エチル］［２−［４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−３’−イソブチル−４−ビフェニリル］エチル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 682 (M-H)- (8) [(2R) -2-hydroxy-2- (4-nitrophenyl) ethyl] [2- [4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -3′-isobutyl- 4-Biphenylyl] ethyl] tertiary butyl carbamate
(-) ESI-MS (m / z): 682 (MH) -

（９） ［２−［３’−シクロペンチル−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］エチル］［（２Ｒ）−２−ヒドロキシ−２−（４−ニトロフェニル）エチル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 694 (M-H)- (9) [2- [3′-Cyclopentyl-4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -4-biphenylyl] ethyl] [(2R) -2-hydroxy-2- (4 -Nitrophenyl) ethyl] tertiary butyl carbamate
(-) ESI-MS (m / z): 694 (MH) -

（１０） ［２−［４’−［［［［２−（ベンジルオキシ）エチル］スルホニル］アミノ］カルボニル］−３’−（シクロヘキシルオキシ）−４−ビフェニリル］エチル］［（２Ｒ）−２−ヒドロキシ−２−（４−ニトロフェニル）エチル］カルバミン酸第三級ブチル (10) [2- [4 ′-[[[[2- (Benzyloxy) ethyl] sulfonyl] amino] carbonyl] -3 ′-(cyclohexyloxy) -4-biphenylyl] ethyl] [(2R) -2- Hydroxy-2- (4-nitrophenyl) ethyl] tertiary butyl carbamate

（１１） ［２−［［３’−（シクロヘキシルオキシ）−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］オキシ］エチル］［（２Ｒ）−２−ヒドロキシ−２−（４−ニトロフェニル）エチル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 740 (M-H)- (11) [2-[[3 ′-(Cyclohexyloxy) -4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -4-biphenylyl] oxy] ethyl] [(2R) -2- Hydroxy-2- (4-nitrophenyl) ethyl] tertiary butyl carbamate
(-) ESI-MS (m / z): 740 (MH) -

（１２） ［２−［［３’−シクロペンチル−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］オキシ］エチル］［（２Ｒ）−２−ヒドロキシ−２−（４−ニトロフェニル）エチル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 710 (M-H)- (12) [2-[[3′-Cyclopentyl-4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -4-biphenylyl] oxy] ethyl] [(2R) -2-hydroxy-2 -(4-Nitrophenyl) ethyl] tertiary butyl carbamate
(-) ESI-MS (m / z): 710 (MH) -

（１３） ［２−［３’−（シクロヘキシルオキシ）−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］エチル］［（２Ｒ）−２−ヒドロキシ−２−（３−ニトロフェニル）エチル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 724 (M-H)- (13) [2- [3 ′-(Cyclohexyloxy) -4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -4-biphenylyl] ethyl] [(2R) -2-hydroxy-2 -(3-Nitrophenyl) ethyl] tertiary butyl carbamate
(-) ESI-MS (m / z): 724 (MH) -

（１４） ４’−［２−［［（１Ｓ，２Ｒ）−２−ヒドロキシ−１−メチル−２−フェニルエチル］アミノ］エチル］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−３−イソプロポキシ−４−ビフェニルカルボキサミド塩酸塩
NMR (200 MHz, DMSO-d6, δ): 0.97 (3H, t, J=6.6Hz), 1.26 (6H, d, J=6.0Hz), 1.7-2.0 (2H, m), 3.0-3.2 (2H, m), 3.3-3.7 (6H, m), 4.74 (1H, m), 4.97 (1H, m), 5.20 (1H, m), 6.13 (1H, m), 7.1-7.5 (9H, m), 7.6-7.9 (3H, m)
ESI-MS (m/z): 555 (M+H) (14) 4 ′-[2-[[(1S, 2R) -2-hydroxy-1-methyl-2-phenylethyl] amino] ethyl] -N-[(3-hydroxypropyl) sulfonyl] -3-iso Propoxy-4-biphenylcarboxamide hydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 0.97 (3H, t, J = 6.6Hz), 1.26 (6H, d, J = 6.0Hz), 1.7-2.0 (2H, m), 3.0-3.2 ( 2H, m), 3.3-3.7 (6H, m), 4.74 (1H, m), 4.97 (1H, m), 5.20 (1H, m), 6.13 (1H, m), 7.1-7.5 (9H, m) , 7.6-7.9 (3H, m)
ESI-MS (m / z): 555 (M + H)

（１５） Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エチル］−３−プロポキシ−４−ビフェニルカルボキサミド二塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.01 (3H, t, J=6.2Hz), 1.7-2.0 (4H, m), 2.8-4.2 (12H, m), 5.24 (1H, m), 7.1-7.4 (4H, m), 7.5-8.0 (4H, m), 8.36 (1H, m), 8.7-9.0 (2H, m)
ESI-MS (m/z): 542 (M+H) (15) N-[(3-hydroxypropyl) sulfonyl] -4 ′-[2-[[(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] ethyl] -3-propoxy-4 -Biphenylcarboxamide dihydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 1.01 (3H, t, J = 6.2Hz), 1.7-2.0 (4H, m), 2.8-4.2 (12H, m), 5.24 (1H, m), 7.1-7.4 (4H, m), 7.5-8.0 (4H, m), 8.36 (1H, m), 8.7-9.0 (2H, m)
ESI-MS (m / z): 542 (M + H)

（１６） ［３−［３’−（シクロヘキシルオキシ）−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］プロピル］［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］カルバミン酸
(-)ESI-MS (m/z): 693 (M-H)- (16) [3- [3 '-(Cyclohexyloxy) -4'-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -4-biphenylyl] propyl] [(2R) -2-hydroxy-2 -Phenylethyl] carbamic acid
(-) ESI-MS (m / z): 693 (MH) -

（１７） ［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］［３−［４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−３’−イソプロポキシ−４−ビフェニリル］プロピル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 653 (M-H)- (17) [(2R) -2-hydroxy-2-phenylethyl] [3- [4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -3′-isopropoxy-4-biphenylyl] Propyl] tertiary butyl carbamate
(-) ESI-MS (m / z): 653 (MH) -

（１８） ［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］［３−［４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−３’−イソブチル−４−ビフェニリル］プロピル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 651 (M-H)- (18) [(2R) -2-hydroxy-2-phenylethyl] [3- [4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -3′-isobutyl-4-biphenylyl] propyl ] Tertiary butyl carbamate
(-) ESI-MS (m / z): 651 (MH) -

（１９） ［３−［３’−シクロペンチル−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］プロピル］［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 663 (M-H)- (19) [3- [3′-Cyclopentyl-4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -4-biphenylyl] propyl] [(2R) -2-hydroxy-2-phenylethyl ] Tertiary butyl carbamate
(-) ESI-MS (m / z): 663 (MH) -

（２０） ［３−［３’−（シクロヘキシルオキシ）−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］プロピル］［（２Ｒ）−２−ヒドロキシ−２−（４−ニトロフェニル）エチル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 738 (M-H)- (20) [3- [3 ′-(Cyclohexyloxy) -4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -4-biphenylyl] propyl] [(2R) -2-hydroxy-2 -(4-Nitrophenyl) ethyl] tertiary butyl carbamate
(-) ESI-MS (m / z): 738 (MH)-

（２１） ［３−［３’−シクロペンチル−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］プロピル］［（２Ｒ）−２−ヒドロキシ−２−（４−ニトロフェニル）エチル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 708 (M-H)- (21) [3- [3′-Cyclopentyl-4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -4-biphenylyl] propyl] [(2R) -2-hydroxy-2- (4 -Nitrophenyl) ethyl] tertiary butyl carbamate
(-) ESI-MS (m / z): 708 (MH) -

（２２） ［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］［３−［４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−３’−イソプロポキシ−４−ビフェニリル］プロピル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 687, 688, 689 (M-H)- (22) [(2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] [3- [4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -3′-isopropoxy- 4-Biphenylyl] propyl] tertiary butyl carbamate
(-) ESI-MS (m / z): 687, 688, 689 (MH) -

（２３） ［３−［３’−（シクロヘキシルオキシ）−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］プロピル］［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 694 (M-H)- (23) [3- [3 ′-(Cyclohexyloxy) -4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -4-biphenylyl] propyl] [(2R) -2-hydroxy-2 -(3-pyridyl) ethyl] tertiary butyl carbamate
(-) ESI-MS (m / z): 694 (MH) -

実施例５
下記の化合物を実施例３と同様の方法にしたがって得た。
（１） ４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エトキシ］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−３−イソプロポキシ−４−ビフェニルカルボキサミド塩酸塩
NMR (400 MHz, DMSO-d6, δ): 1.37 (6H, d, J=5.9Hz), 1.85-1.92 (2H, m), 3.10 (1H, dd, J=10.6, 12.4Hz), 3.27 (1H, dd, J=1.8, 12.4Hz), 3.44-3.57 (6H, m), 4.35-4.44 (2H, m), 4.75 (1H, t, J=5.1Hz), 4.94-5.06 (2H, m), 6.23 (1H, d, J=3.7Hz), 7.12 (2H, d, J=8.8Hz), 7.31-7.44 (7H, m), 7.71 (1H, d, J=8.1Hz), 7.75 (2H, d, J=8.8Hz), 9.21 (2H, br), 11.0 (1H, br)
(-)ESI-MS (m/z): 555 (M-H)- Example 5
The following compound was obtained according to the same method as in Example 3.
(1) 4 ′-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethoxy] -N-[(3-hydroxypropyl) sulfonyl] -3-isopropoxy-4-biphenylcarboxamide Hydrochloride
NMR (400 MHz, DMSO-d 6 , δ): 1.37 (6H, d, J = 5.9Hz), 1.85-1.92 (2H, m), 3.10 (1H, dd, J = 10.6, 12.4Hz), 3.27 ( 1H, dd, J = 1.8, 12.4Hz), 3.44-3.57 (6H, m), 4.35-4.44 (2H, m), 4.75 (1H, t, J = 5.1Hz), 4.94-5.06 (2H, m) , 6.23 (1H, d, J = 3.7Hz), 7.12 (2H, d, J = 8.8Hz), 7.31-7.44 (7H, m), 7.71 (1H, d, J = 8.1Hz), 7.75 (2H, d, J = 8.8Hz), 9.21 (2H, br), 11.0 (1H, br)
(-) ESI-MS (m / z): 555 (MH) -

（２） ３−（シクロヘキシルオキシ）−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エトキシ］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４−ビフェニルカルボキサミド塩酸塩
NMR (400 MHz, DMSO-d6, δ): 1.30-1.63 (6H, m), 1.69-1.77 (2H, m), 1.84-1.91 (2H, m), 1.93-2.01 (2H, m), 3.10 (1H, dd, J=10.6, 12.4Hz), 3.27 (1H, dd, J=2.2, 12.4Hz), 3.44-3.58 (6H, m), 4.35-4.43 (2H, m), 4.74 (1H, t, J=5.1Hz), 4.79-4.85 (1H, m), 5.01-5.05 (1H, m), 6.22 (1H, d, J=3.7Hz), 7.12 (2H, d, J=8.8Hz), 7.31-7.43 (7H, m), 7.74 (1H, d, J=8.1Hz), 7.75 (1H, d, J=8.8Hz), 9.20 (2H, br), 11.0 (1H, br)
(-)ESI-MS (m/z): 595 (M-H)- (2) 3- (Cyclohexyloxy) -4 ′-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethoxy] -N-[(3-hydroxypropyl) sulfonyl] -4- Biphenyl carboxamide hydrochloride
NMR (400 MHz, DMSO-d 6 , δ): 1.30-1.63 (6H, m), 1.69-1.77 (2H, m), 1.84-1.91 (2H, m), 1.93-2.01 (2H, m), 3.10 (1H, dd, J = 10.6, 12.4Hz), 3.27 (1H, dd, J = 2.2, 12.4Hz), 3.44-3.58 (6H, m), 4.35-4.43 (2H, m), 4.74 (1H, t , J = 5.1Hz), 4.79-4.85 (1H, m), 5.01-5.05 (1H, m), 6.22 (1H, d, J = 3.7Hz), 7.12 (2H, d, J = 8.8Hz), 7.31 -7.43 (7H, m), 7.74 (1H, d, J = 8.1Hz), 7.75 (1H, d, J = 8.8Hz), 9.20 (2H, br), 11.0 (1H, br)
(-) ESI-MS (m / z): 595 (MH) -

（３） ３−シクロペンチル−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エトキシ］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４−ビフェニルカルボキサミド塩酸塩
NMR (400 MHz, DMSO-d6, δ): 1.60-1.71 (4H, m), 1.77-1.91 (4H, m), 1.99-2.07 (2H, m), 3.08-3.13 (1H, m), 3.25-3.31 (2H, m), 3.44-3.47 (2H, m), 3.51-3.57 (4H, m), 4.34-4.42 (2H, m), 4.78 (1H, br), 5.01-5.05 (1H, m), 6.23 (1H, d, J=3.7Hz), 7.11 (2H, d, J=8.8Hz), 7.31-7.46 (6H, m), 7.53 (1H, dd, J=1.5, 8.1Hz), 7.62 (1H, d, J=1.5Hz), 7.70 (2H, d, J=8.8Hz), 9.06 (1H, br), 9.21 (1H, br), 12.1 (1H, br)
(-)ESI-MS (m/z): 565 (M-H)- (3) 3-cyclopentyl-4 ′-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethoxy] -N-[(3-hydroxypropyl) sulfonyl] -4-biphenylcarboxamide hydrochloride salt
NMR (400 MHz, DMSO-d 6 , δ): 1.60-1.71 (4H, m), 1.77-1.91 (4H, m), 1.99-2.07 (2H, m), 3.08-3.13 (1H, m), 3.25 -3.31 (2H, m), 3.44-3.47 (2H, m), 3.51-3.57 (4H, m), 4.34-4.42 (2H, m), 4.78 (1H, br), 5.01-5.05 (1H, m) , 6.23 (1H, d, J = 3.7Hz), 7.11 (2H, d, J = 8.8Hz), 7.31-7.46 (6H, m), 7.53 (1H, dd, J = 1.5, 8.1Hz), 7.62 ( 1H, d, J = 1.5Hz), 7.70 (2H, d, J = 8.8Hz), 9.06 (1H, br), 9.21 (1H, br), 12.1 (1H, br)
(-) ESI-MS (m / z): 565 (MH) -

（４） ４’−［２−［［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エトキシ］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−３−イソプロポキシ−４−ビフェニルカルボキサミド塩酸塩
NMR (400 MHz, DMSO-d6, δ): 1.37 (6H, d, J=6.2Hz), 1.84-1.92 (2H, m), 3.12 (1H, dd, J=10.3, 12.4Hz), 3.28-3.31 (1H, m), 3.44 (2H, t, J=5.1Hz), 3.49-3.57 (4H, m), 4.34-4.42 (2H, m), 4.74 (1H, t, J=5.1HZ), 4.94-5.07 (2H, m), 6.36 (1H, d, J=4.0Hz), 7.12 (2H, d, J=8.8Hz), 7.33-7.49 (6H, m), 7.71 (1H, d, J=8.1Hz), 7.76 (2H, d, J=8.8Hz), 9.12 (2H, br), 11.1 (1H, br)
(-)ESI-MS (m/z): 589 (M-H)- (4) 4 ′-[2-[[(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethoxy] -N-[(3-hydroxypropyl) sulfonyl] -3-isopropoxy- 4-biphenylcarboxamide hydrochloride
NMR (400 MHz, DMSO-d 6 , δ): 1.37 (6H, d, J = 6.2Hz), 1.84-1.92 (2H, m), 3.12 (1H, dd, J = 10.3, 12.4Hz), 3.28- 3.31 (1H, m), 3.44 (2H, t, J = 5.1Hz), 3.49-3.57 (4H, m), 4.34-4.42 (2H, m), 4.74 (1H, t, J = 5.1HZ), 4.94 -5.07 (2H, m), 6.36 (1H, d, J = 4.0Hz), 7.12 (2H, d, J = 8.8Hz), 7.33-7.49 (6H, m), 7.71 (1H, d, J = 8.1 Hz), 7.76 (2H, d, J = 8.8Hz), 9.12 (2H, br), 11.1 (1H, br)
(-) ESI-MS (m / z): 589 (MH) -

（５） ４’−［２−［［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エトキシ］−３−シクロペンチル−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４−ビフェニルカルボキサミド塩酸塩
NMR (400 MHz, DMSO-d6, δ): 1.60-1.70 (4H, m), 1.77-1.91 (4H, m), 1.99-2.06 (2H, m), 3.12 (1H, dd, J=10.6, 12.4Hz), 3.27-3.31 (1H, m), 3.44 (2H, t, J=4.8Hz), 3.51-3.57 (4H, m), 4.32-4.41 (2H, m), 4.76 (1H, t, J=4.8Hz), 5.02-5.06 (1H, m), 6.35 (1H, d, J=4.0Hz), 7.10 (2H, d, J=8.8Hz), 7.37-7.54 (6H, m), 7.62 (1H, d, J=1.5Hz), 7.70 (2H, d, J=8.8Hz), 9.04 (2H, br), 12.1 (1H, br)
(-)ESI-MS (m/z): 599 (M-H)- (5) 4 ′-[2-[[(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethoxy] -3-cyclopentyl-N-[(3-hydroxypropyl) sulfonyl] -4 -Biphenylcarboxamide hydrochloride
NMR (400 MHz, DMSO-d 6 , δ): 1.60-1.70 (4H, m), 1.77-1.91 (4H, m), 1.99-2.06 (2H, m), 3.12 (1H, dd, J = 10.6, 12.4Hz), 3.27-3.31 (1H, m), 3.44 (2H, t, J = 4.8Hz), 3.51-3.57 (4H, m), 4.32-4.41 (2H, m), 4.76 (1H, t, J = 4.8Hz), 5.02-5.06 (1H, m), 6.35 (1H, d, J = 4.0Hz), 7.10 (2H, d, J = 8.8Hz), 7.37-7.54 (6H, m), 7.62 (1H , d, J = 1.5Hz), 7.70 (2H, d, J = 8.8Hz), 9.04 (2H, br), 12.1 (1H, br)
(-) ESI-MS (m / z): 599 (MH) -

（６） ３−（シクロヘキシルオキシ）−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エトキシ］−４−ビフェニルカルボキサミド二塩酸塩
NMR (400 MHz, DMSO-d6, δ): 1.31-1.63 (6H, m), 1.69-1.78 (2H, m), 1.84-1.91 (2H, m), 1.93-2.00 (2H, m), 3.23-3.58 (8H, m), 4.36-4.44 (2H, m), 4.79-4.85 (1H, m), 5.27 (1H, dd, J=2.9, 9.5Hz), 6.68 (1H, br), 7.12 (2H, d, J=8.8Hz), 7.34 (1H, dd, J=1.5, 8.1Hz), 7.40 (1H, d, J=1.5Hz), 7.74 (1H, d, J=8.1Hz), 7.75 (2H, d, J=8.8Hz), 7.86 (1H, dd, J=5.5, 8.1Hz), 8.34 (1H, d, J=8.1Hz), 8.78 (1H, dd, J=1.5, 5.5Hz), 8.84 (1H, d, J=1.5Hz), 9.23 (1H, br)
(-)ESI-MS (m/z): 596 (M-H)- (6) 3- (Cyclohexyloxy) -N-[(3-hydroxypropyl) sulfonyl] -4 ′-[2-[[(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] ethoxy ] -4-Biphenylcarboxamide dihydrochloride
NMR (400 MHz, DMSO-d 6 , δ): 1.31-1.63 (6H, m), 1.69-1.78 (2H, m), 1.84-1.91 (2H, m), 1.93-2.00 (2H, m), 3.23 -3.58 (8H, m), 4.36-4.44 (2H, m), 4.79-4.85 (1H, m), 5.27 (1H, dd, J = 2.9, 9.5Hz), 6.68 (1H, br), 7.12 (2H , d, J = 8.8Hz), 7.34 (1H, dd, J = 1.5, 8.1Hz), 7.40 (1H, d, J = 1.5Hz), 7.74 (1H, d, J = 8.1Hz), 7.75 (2H , d, J = 8.8Hz), 7.86 (1H, dd, J = 5.5, 8.1Hz), 8.34 (1H, d, J = 8.1Hz), 8.78 (1H, dd, J = 1.5, 5.5Hz), 8.84 (1H, d, J = 1.5Hz), 9.23 (1H, br)
(-) ESI-MS (m / z): 596 (MH) -

（７） ４’−［２−［［（２Ｒ）−２−（４−アミノフェニル）−２−ヒドロキシエチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４−ビフェニルカルボキサミド二塩酸塩
NMR (400 MHz, DMSO-d6, δ): 1.30-1.63 (6H, m), 1.71-1.76 (2H, m), 1.84-1.98 (4H, m), 3.00-3.12 (3H, m), 3.16-3.26 (3H, m), 4.49-3.58 (4H, m), 3.73 (1H, s), 4.78-4.82 (1H, m), 4.97-4.99 (1H, m), 6.25 (1H, s), 7.22-7.24 (2H, m), 7.34-7.43 (6H, m), 7.72-7.74 (3H, m), 8.89 (1H, br s), 9.20 (1H, br s), 9.57 (3H, br), 11.2 (1H, br s)
(-)ESI-MS (m/z): 594 (M-H)- (7) 4 ′-[2-[[(2R) -2- (4-aminophenyl) -2-hydroxyethyl] amino] ethyl] -3- (cyclohexyloxy) -N-[(3-hydroxypropyl) Sulfonyl] -4-biphenylcarboxamide dihydrochloride
NMR (400 MHz, DMSO-d 6 , δ): 1.30-1.63 (6H, m), 1.71-1.76 (2H, m), 1.84-1.98 (4H, m), 3.00-3.12 (3H, m), 3.16 -3.26 (3H, m), 4.49-3.58 (4H, m), 3.73 (1H, s), 4.78-4.82 (1H, m), 4.97-4.99 (1H, m), 6.25 (1H, s), 7.22 -7.24 (2H, m), 7.34-7.43 (6H, m), 7.72-7.74 (3H, m), 8.89 (1H, br s), 9.20 (1H, br s), 9.57 (3H, br), 11.2 (1H, br s)
(-) ESI-MS (m / z): 594 (MH) -

（８） ４’−［２−［［（２Ｒ）−２−（４−アミノフェニル）−２−ヒドロキシエチル］アミノ］エチル］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−３−イソブチル−４−ビフェニルカルボキサミド二塩酸塩
NMR (400 MHz, DMSO-d6, δ): 0.87 (6H, d, J=6.6Hz), 1.79-1.91 (3H, m), 2.73 (1H, d, J=7.0Hz), 3.00-3.12 (3H, m), 3.16-3.26 (3H, m), 3.51-3.57 (4H, m), 4.94 (1H, dd, J=2.2, 9.9Hz), 6.25 (1H, br), 7.22 (2H, d, J=8.1Hz), 7.38 (2H, d, J=8.1Hz), 7.42 (2H, d, J=8.1Hz), 7.53-7.61 (3H, m), 7.70 (2H, d, J=8.1Hz), 8.88 (1H, br), 9.17 (1H, br), 9.48 (3H, br), 12.1 (1H, br)
(-)ESI-MS (m/z): 552 (M-H)- (8) 4 ′-[2-[[(2R) -2- (4-aminophenyl) -2-hydroxyethyl] amino] ethyl] -N-[(3-hydroxypropyl) sulfonyl] -3-isobutyl- 4-biphenylcarboxamide dihydrochloride
NMR (400 MHz, DMSO-d 6 , δ): 0.87 (6H, d, J = 6.6Hz), 1.79-1.91 (3H, m), 2.73 (1H, d, J = 7.0Hz), 3.00-3.12 ( 3H, m), 3.16-3.26 (3H, m), 3.51-3.57 (4H, m), 4.94 (1H, dd, J = 2.2, 9.9Hz), 6.25 (1H, br), 7.22 (2H, d, J = 8.1Hz), 7.38 (2H, d, J = 8.1Hz), 7.42 (2H, d, J = 8.1Hz), 7.53-7.61 (3H, m), 7.70 (2H, d, J = 8.1Hz) , 8.88 (1H, br), 9.17 (1H, br), 9.48 (3H, br), 12.1 (1H, br)
(-) ESI-MS (m / z): 552 (MH) -

（９） ４’−［２−［［（２Ｒ）−２−（４−アミノフェニル）−２−ヒドロキシエチル］アミノ］エチル］−３−シクロペンチル−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４−ビフェニルカルボキサミド二塩酸塩
NMR (400 MHz, DMSO-d6, δ): 1.60-1.71 (4H, m), 1.76-1.91 (4H, m), 1.98-2.07 (2H, m), 3.0-3.34 (7H, m), 3.51-3.58 (4H, m), 4.96-4.99 (1H, m), 6.25 (1H, br), 7.22 (2H, d, J=8.1Hz), 7.37-7.48 (5H, m), 7.56 (1H, dd, J=1.5, 8.1Hz), 7.64 (1H, d, J=1.5Hz), 7.69 (2H, d, J=8.4Hz), 8.89 (1H, br), 9.18 (1H, br), 9.51 (3H, br), 12.2 (1H, br)
(-)ESI-MS (m/z): 564 (M-H)- (9) 4 ′-[2-[[(2R) -2- (4-aminophenyl) -2-hydroxyethyl] amino] ethyl] -3-cyclopentyl-N-[(3-hydroxypropyl) sulfonyl]- 4-biphenylcarboxamide dihydrochloride
NMR (400 MHz, DMSO-d 6 , δ): 1.60-1.71 (4H, m), 1.76-1.91 (4H, m), 1.98-2.07 (2H, m), 3.0-3.34 (7H, m), 3.51 -3.58 (4H, m), 4.96-4.99 (1H, m), 6.25 (1H, br), 7.22 (2H, d, J = 8.1Hz), 7.37-7.48 (5H, m), 7.56 (1H, dd , J = 1.5, 8.1Hz), 7.64 (1H, d, J = 1.5Hz), 7.69 (2H, d, J = 8.4Hz), 8.89 (1H, br), 9.18 (1H, br), 9.51 (3H , br), 12.2 (1H, br)
(-) ESI-MS (m / z): 564 (MH) -

（１０） ４’−［２−［［（２Ｒ）−２−（４−アミノフェニル）−２−ヒドロキシエチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−Ｎ−［（２−ヒドロキシエチル）スルホニル］−４−ビフェニルカルボキサミド二塩酸塩
NMR (400 MHz, DMSO-d6, δ): 1.31-1.63 (6H, m), 1.69-1.78 (2H, m), 1.92-2.01 (2H, m),3.00-3.27 (6H, m), 3.65-3.85 (4H, m), 6.27 (1H, br), 7.29 (2H, d, J=8.4Hz), 7.36 (1H, dd, J=1.5, 8.1Hz), 7.39 (2H, d, J=8.4Hz), 7.42 (1H, d, J=1.5Hz), 7.45 (2H, d, J=8.4Hz), 7.73 (2H, d, J=8.4Hz), 7.78 (1H, d, J=8.1Hz), 8.95 (1H, br), 9.31 (1H, br), 9.86 (3H, br), 11.1 (1H, br)
(-)ESI-MS (m/z): 580 (M-H)- (10) 4 ′-[2-[[(2R) -2- (4-aminophenyl) -2-hydroxyethyl] amino] ethyl] -3- (cyclohexyloxy) -N-[(2-hydroxyethyl) Sulfonyl] -4-biphenylcarboxamide dihydrochloride
NMR (400 MHz, DMSO-d 6 , δ): 1.31-1.63 (6H, m), 1.69-1.78 (2H, m), 1.92-2.01 (2H, m), 3.00-3.27 (6H, m), 3.65 -3.85 (4H, m), 6.27 (1H, br), 7.29 (2H, d, J = 8.4Hz), 7.36 (1H, dd, J = 1.5, 8.1Hz), 7.39 (2H, d, J = 8.4 Hz), 7.42 (1H, d, J = 1.5Hz), 7.45 (2H, d, J = 8.4Hz), 7.73 (2H, d, J = 8.4Hz), 7.78 (1H, d, J = 8.1Hz) , 8.95 (1H, br), 9.31 (1H, br), 9.86 (3H, br), 11.1 (1H, br)
(-) ESI-MS (m / z): 580 (MH) -

（１１） ４’−［２−［［（２Ｒ）−２−（４−アミノフェニル）−２−ヒドロキシエチル］アミノ］エトキシ］−３−（シクロヘキシルオキシ）−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４−ビフェニルカルボキサミド二塩酸塩
NMR (400 MHz, DMSO-d6, δ): 1.31-1.63 (6H, m), 1.69-1.77 (2H, m), 1.84-1.91 (2H, m), 1.93-2.00 (2H, m), 3.04-3.30 (4H, m), 3.49-3.58 (4H, m), 4.35-4.44 (2H, m), 4.79-4.85 (1H, m), 5.04 (1H, dd, J=2.2, 10.3Hz), 6.27 (1H, br), 7.12 (2H, d, J=8.8Hz), 7.27 (2H, d, J=8.1Hz), 7.34 (1H, dd, J=1.5, 8.1Hz), 7.41 (1H, d, J=1.5Hz), 7.45 (2H, d, J=8.1Hz), 7.74 (1H, d, J=8.1Hz), 7.75 (1H, d, J=8.4Hz), 9.03 (1H, br), 9.31 (1H, br), 9.79 (3H, br), 11.1 (1H, br)
(-)ESI-MS (m/z): 610 (M-H)- (11) 4 ′-[2-[[(2R) -2- (4-aminophenyl) -2-hydroxyethyl] amino] ethoxy] -3- (cyclohexyloxy) -N-[(3-hydroxypropyl) Sulfonyl] -4-biphenylcarboxamide dihydrochloride
NMR (400 MHz, DMSO-d 6 , δ): 1.31-1.63 (6H, m), 1.69-1.77 (2H, m), 1.84-1.91 (2H, m), 1.93-2.00 (2H, m), 3.04 -3.30 (4H, m), 3.49-3.58 (4H, m), 4.35-4.44 (2H, m), 4.79-4.85 (1H, m), 5.04 (1H, dd, J = 2.2, 10.3Hz), 6.27 (1H, br), 7.12 (2H, d, J = 8.8Hz), 7.27 (2H, d, J = 8.1Hz), 7.34 (1H, dd, J = 1.5, 8.1Hz), 7.41 (1H, d, J = 1.5Hz), 7.45 (2H, d, J = 8.1Hz), 7.74 (1H, d, J = 8.1Hz), 7.75 (1H, d, J = 8.4Hz), 9.03 (1H, br), 9.31 (1H, br), 9.79 (3H, br), 11.1 (1H, br)
(-) ESI-MS (m / z): 610 (MH) -

（１２） ４’−［２−［［（２Ｒ）−２−（４−アミノフェニル）−２−ヒドロキシエチル］アミノ］エトキシ］−３−シクロペンチル−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４−ビフェニルカルボキサミド二塩酸塩
NMR (400 MHz, DMSO-d6, δ): 1.60-1.71 (4H, m), 1.76-1.91 (4H, m), 1.98-2.07 (2H, m), 3.05-3.35 (5H, m), 3.51-3.58 (4H, m), 4.33-4.42 (2H, m), 5.02 (1H, dd, J=2.2, 10.3Hz), 6.25 (1H, br), 7.11 (2H, d, J=8.8Hz), 7.24 (2H, d, J=7.7Hz), 7.42-7.46 (3H, m), 7.53 (1H, dd, J=1.5, 8.1Hz), 7.62 (1H, d, J=1.5Hz), 7.70 (2H, d, J=8.8Hz), 8.99 (1H, br), 9.23 (1H, br), 9.54 (3H, br), 12.1 (1H, br)
(-)ESI-MS (m/z): 580 (M-H)- (12) 4 ′-[2-[[(2R) -2- (4-aminophenyl) -2-hydroxyethyl] amino] ethoxy] -3-cyclopentyl-N-[(3-hydroxypropyl) sulfonyl]- 4-biphenylcarboxamide dihydrochloride
NMR (400 MHz, DMSO-d 6 , δ): 1.60-1.71 (4H, m), 1.76-1.91 (4H, m), 1.98-2.07 (2H, m), 3.05-3.35 (5H, m), 3.51 -3.58 (4H, m), 4.33-4.42 (2H, m), 5.02 (1H, dd, J = 2.2, 10.3Hz), 6.25 (1H, br), 7.11 (2H, d, J = 8.8Hz), 7.24 (2H, d, J = 7.7Hz), 7.42-7.46 (3H, m), 7.53 (1H, dd, J = 1.5, 8.1Hz), 7.62 (1H, d, J = 1.5Hz), 7.70 (2H , d, J = 8.8Hz), 8.99 (1H, br), 9.23 (1H, br), 9.54 (3H, br), 12.1 (1H, br)
(-) ESI-MS (m / z): 580 (MH) -

（１３） ４’−［２−［［（２Ｒ）−２−（３−アミノフェニル）−２−ヒドロキシエチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４−ビフェニルカルボキサミド二塩酸塩
NMR (400 MHz, DMSO-d6, δ): 1.30-1.63 (7H, m), 1.68-1.77 (2H, m), 1.84-1.91 (2H, m), 1.92-1.99 (2H, m), 2.95-3.28 (6H, m), 3.49-3.56 (4H, m), 4.81 (1H, heptuplet, J=4.0Hz), 5.04 (1H, dd, J=2.2, 10.3Hz), 6.38 (1H, br), 7.20 (1H, d, J=8.1Hz), 7.28-7.46 (7H, m), 7.72-7.74 (3H, m), 8.97 (1H, br), 9.38 (1H, br), 9.88 (3H, br), 11.2 (1H, br)
(-)ESI-MS (m/z): 594 (M-H)- (13) 4 ′-[2-[[(2R) -2- (3-aminophenyl) -2-hydroxyethyl] amino] ethyl] -3- (cyclohexyloxy) -N-[(3-hydroxypropyl) Sulfonyl] -4-biphenylcarboxamide dihydrochloride
NMR (400 MHz, DMSO-d 6 , δ): 1.30-1.63 (7H, m), 1.68-1.77 (2H, m), 1.84-1.91 (2H, m), 1.92-1.99 (2H, m), 2.95 -3.28 (6H, m), 3.49-3.56 (4H, m), 4.81 (1H, heptuplet, J = 4.0Hz), 5.04 (1H, dd, J = 2.2, 10.3Hz), 6.38 (1H, br), 7.20 (1H, d, J = 8.1Hz), 7.28-7.46 (7H, m), 7.72-7.74 (3H, m), 8.97 (1H, br), 9.38 (1H, br), 9.88 (3H, br) , 11.2 (1H, br)
(-) ESI-MS (m / z): 594 (MH) -

（１４） ３−（シクロヘプチルオキシ）−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エチル］−４−ビフェニルカルボキサミド二塩酸塩
NMR (400 MHz, DMSO-d6, δ): 1.43-1.61 (6H, m), 1.64-1.73 (2H, m), 1.76-1.91 (4H, m), 2.00-2.09 (2H, m), 3.04-3.42 (4H, m), 3.49-3.56 (4H, m), 4.93-4.98 (1H, m), 5.25 (1H, dd, J=2.9, 9.2Hz), 6.72 (1H, br), 7.34-7.36 (2H, m), 7.40 (2H, d, J=8.1Hz), 7.72 (1H, d, J=7.7Hz), 7.74 (2H, d, J=8.1Hz), 7.90 (1H, dd, J=5.5, 8.1Hz), 8.38 (1H, d, J=7.7Hz), 8.80 (1H, dd, J=1.5, 5.5Hz), 8.86 (1H, d, J=1.5Hz), 9.16 (1H, br), 9.31 (1H, br), 11.2 (1H, br s)
(-)ESI-MS (m/z): 594 (M-H)- (14) 3- (Cycloheptyloxy) -N-[(3-hydroxypropyl) sulfonyl] -4 ′-[2-[[(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] Ethyl] -4-biphenylcarboxamide dihydrochloride
NMR (400 MHz, DMSO-d 6 , δ): 1.43-1.61 (6H, m), 1.64-1.73 (2H, m), 1.76-1.91 (4H, m), 2.00-2.09 (2H, m), 3.04 -3.42 (4H, m), 3.49-3.56 (4H, m), 4.93-4.98 (1H, m), 5.25 (1H, dd, J = 2.9, 9.2Hz), 6.72 (1H, br), 7.34-7.36 (2H, m), 7.40 (2H, d, J = 8.1Hz), 7.72 (1H, d, J = 7.7Hz), 7.74 (2H, d, J = 8.1Hz), 7.90 (1H, dd, J = 5.5, 8.1Hz), 8.38 (1H, d, J = 7.7Hz), 8.80 (1H, dd, J = 1.5, 5.5Hz), 8.86 (1H, d, J = 1.5Hz), 9.16 (1H, br) , 9.31 (1H, br), 11.2 (1H, br s)
(-) ESI-MS (m / z): 594 (MH) -

（１５） ４’−［２−［［（２Ｒ）−２−（６−クロロ−３−ピリジル）−２−ヒドロキシエチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−Ｎ−［（２−ヒドロキシエチル）スルホニル］−４−ビフェニルカルボキサミド塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.24-2.02 (8H, m), 3.02-3.54 (6H, m), 3.67 (2H, t, J=6.0Hz), 3.84 (2H, t, J=5.8Hz), 4.76-4.87 (1H, m), 5.08-5.16 (1H, m), 6.48 (1H, br s), 7.32-7.44 (4H, m), 7.57 (1H, d, J=8.5Hz), 7.67-7.80 (3H, m), 7.91 (1H, dd, J=2.3, 8.0Hz), 8.46 (1H, d, J=2.0Hz), 9.07 (1H, br s), 9.31 (1H, br s), 11.10 (1H, s)
(-)ESI-MS (m/z): 600 (M-H)- (15) 4 ′-[2-[[(2R) -2- (6-Chloro-3-pyridyl) -2-hydroxyethyl] amino] ethyl] -3- (cyclohexyloxy) -N-[(2- Hydroxyethyl) sulfonyl] -4-biphenylcarboxamide hydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 1.24-2.02 (8H, m), 3.02-3.54 (6H, m), 3.67 (2H, t, J = 6.0Hz), 3.84 (2H, t, J = 5.8Hz), 4.76-4.87 (1H, m), 5.08-5.16 (1H, m), 6.48 (1H, br s), 7.32-7.44 (4H, m), 7.57 (1H, d, J = 8.5Hz ), 7.67-7.80 (3H, m), 7.91 (1H, dd, J = 2.3, 8.0Hz), 8.46 (1H, d, J = 2.0Hz), 9.07 (1H, br s), 9.31 (1H, br s), 11.10 (1H, s)
(-) ESI-MS (m / z): 600 (MH) -

（１６） ４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エチル］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−３−イソブトキシ−４−ビフェニルカルボキサミド塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.04 (6H, d, J=7.0Hz), 1.80-1.94 (2H, m), 2.03-2.17 (1H, m), 2.99-3.30 (6H, m), 3.46-3.59 (4H, m), 4.03 (2H, d, J=6.0Hz), 4.74 (1H, t, J=5.0Hz), 4.96-5.05 (1H, m), 6.23 (1H, d, J=3.5Hz), 7.30-7.41 (9H, m), 7.67-7.77 (3H, m), 9.16 （1H, br s)
(-)ESI-MS (m/z): 553 (M-H)- (16) 4 ′-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethyl] -N-[(3-hydroxypropyl) sulfonyl] -3-isobutoxy-4-biphenylcarboxamide hydrochloride salt
NMR (200 MHz, DMSO-d 6 , δ): 1.04 (6H, d, J = 7.0Hz), 1.80-1.94 (2H, m), 2.03-2.17 (1H, m), 2.99-3.30 (6H, m ), 3.46-3.59 (4H, m), 4.03 (2H, d, J = 6.0Hz), 4.74 (1H, t, J = 5.0Hz), 4.96-5.05 (1H, m), 6.23 (1H, d, J = 3.5Hz), 7.30-7.41 (9H, m), 7.67-7.77 (3H, m), 9.16 (1H, br s)
(-) ESI-MS (m / z): 553 (MH) -

（１７） ３−（シクロヘキシルオキシ）−Ｎ−［（２−ヒドロキシエチル）スルホニル］−４’−［２−［［（１Ｓ，２Ｒ）−２−ヒドロキシ−１−メチル−２−フェニルエチル］アミノ］エチル］−４−ビフェニルカルボキサミド塩酸塩
NMR (200 MHz, DMSO-d6, δ): 0.97 (3H, d, J=7.0Hz), 1.33-2.02 (10H, m), 3.07-3.50 (5H, m), 3.66 (2H, t, J=6.0Hz), 3.79-3.88 (2H, m), 4.76-4.88 (1H, m), 4.99-5.11 (1H, m), 5.22 (1H, br s), 6.15 (1H, d, J=4.0Hz), 7.29-7.45 (9H, m), 7.71-7.81 (3H, m), 8.97 (2H, br s), 11.10 (1H, br s)
(-)ESI-MS (m/z): 579 (M-H)- (17) 3- (Cyclohexyloxy) -N-[(2-hydroxyethyl) sulfonyl] -4 ′-[2-[[(1S, 2R) -2-hydroxy-1-methyl-2-phenylethyl] amino ] Ethyl] -4-biphenylcarboxamide hydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 0.97 (3H, d, J = 7.0Hz), 1.33-2.02 (10H, m), 3.07-3.50 (5H, m), 3.66 (2H, t, J = 6.0Hz), 3.79-3.88 (2H, m), 4.76-4.88 (1H, m), 4.99-5.11 (1H, m), 5.22 (1H, br s), 6.15 (1H, d, J = 4.0Hz ), 7.29-7.45 (9H, m), 7.71-7.81 (3H, m), 8.97 (2H, br s), 11.10 (1H, br s)
(-) ESI-MS (m / z): 579 (MH) -

（１８） ３−シクロペンチル−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エチル］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４−ビフェニルカルボキサミド塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.59-2.10 (10H, m), 2.99-3.30 (7H, m), 3.18-3.61 (4H, m), 4.73-4.81 (1H, m), 4.95-5.04 (1H, m), 6.23 (1H, d, J=4.0Hz), 7.32-7.58 (9H, m), 7.64-7.71 (3H, m), 8.91 (1H, br s), 9.24 (1H, br s), 12.15 (1H, br s)
(-)ESI-MS (m/z): 549 (M-H)- (18) 3-cyclopentyl-4 ′-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethyl] -N-[(3-hydroxypropyl) sulfonyl] -4-biphenylcarboxamide hydrochloride salt
NMR (200 MHz, DMSO-d 6 , δ): 1.59-2.10 (10H, m), 2.99-3.30 (7H, m), 3.18-3.61 (4H, m), 4.73-4.81 (1H, m), 4.95 -5.04 (1H, m), 6.23 (1H, d, J = 4.0Hz), 7.32-7.58 (9H, m), 7.64-7.71 (3H, m), 8.91 (1H, br s), 9.24 (1H, br s), 12.15 (1H, br s)
(-) ESI-MS (m / z): 549 (MH) -

（１９） ３−（シクロヘキシルオキシ）−Ｎ−［（エチルアミノ）スルホニル］−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エチル］−４−ビフェニルカルボキサミド二塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.09 (3H, t, J=7.0Hz), 1.29-1.81 (7H, m), 1.91-2.04 (2H, m), 2.94-3.46 (8H, m), 4.77-4.90 (1H, m), 5.25-5.34 (1H, m), 7.34-7.42 (4H, m), 7.71-7.80 (3H, m), 7.907.99 (2H, m), 8.46 (1H, d, J=8Hz), 8.82-8.89 (2H, m), 9.25 (1H, br s), 9.40 (1H, br s), 10.90 (1H, s)
(-)ESI-MS (m/z): 565 (M-H)- (19) 3- (Cyclohexyloxy) -N-[(ethylamino) sulfonyl] -4 ′-[2-[[(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] ethyl]- 4-biphenylcarboxamide dihydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 1.09 (3H, t, J = 7.0Hz), 1.29-1.81 (7H, m), 1.91-2.04 (2H, m), 2.94-3.46 (8H, m ), 4.77-4.90 (1H, m), 5.25-5.34 (1H, m), 7.34-7.42 (4H, m), 7.71-7.80 (3H, m), 7.907.99 (2H, m), 8.46 (1H , d, J = 8Hz), 8.82-8.89 (2H, m), 9.25 (1H, br s), 9.40 (1H, br s), 10.90 (1H, s)
(-) ESI-MS (m / z): 565 (MH) -

（２０） ３−（シクロヘキシルアミノ）−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エトキシ］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４−ビフェニルカルボキサミド二塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.26-1.89 (12H, m), 3.00-3.71 (9H, m), 4.35-4.43 (2H, m), 5.03 (1H, d, J=7.5Hz), 6.82 (1H, d, J=8.5Hz), 6.94 (1H, s), 7.10 (2H, d, J=8.5Hz), 7.25-7.49 (5H, m), 7.70 (2H, d, J=8.5Hz), 7.81 (1H, d, J=8.5Hz), 9.00 (1H, br s), 9.26 (1H, br s)
(-)ESI-MS (m/z): 594 (M-H)- (20) 3- (Cyclohexylamino) -4 ′-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethoxy] -N-[(3-hydroxypropyl) sulfonyl] -4- Biphenyl carboxamide dihydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 1.26-1.89 (12H, m), 3.00-3.71 (9H, m), 4.35-4.43 (2H, m), 5.03 (1H, d, J = 7.5Hz ), 6.82 (1H, d, J = 8.5Hz), 6.94 (1H, s), 7.10 (2H, d, J = 8.5Hz), 7.25-7.49 (5H, m), 7.70 (2H, d, J = 8.5Hz), 7.81 (1H, d, J = 8.5Hz), 9.00 (1H, br s), 9.26 (1H, br s)
(-) ESI-MS (m / z): 594 (MH) -

（２１） ４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エトキシ］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−３−（イソプロピルチオ）−４−ビフェニルカルボキサミド塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.25 (6H, d, J=6.5Hz), 1.85-1.99 (2H, m), 3.11-3.72 (9H, m), 4.32-4.45 (2H, m), 4.75 (1H, br s), 5.03 (1H, d, J=10Hz), 6.22 (1H, d, J=3.5Hz), 7.12 (2H, d, J=8.5Hz), 7.31-7.43 (5H, m), 7.53-7.62 (2H, m), 7.71-7.75 (3H, m), 9.00 (1H, br s), 9.26 (1H, br s), 12.11 (1H, br s)
(-)ESI-MS (m/z): 571 (M-H)- (21) 4 '-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethoxy] -N-[(3-hydroxypropyl) sulfonyl] -3- (isopropylthio) -4- Biphenyl carboxamide hydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 1.25 (6H, d, J = 6.5Hz), 1.85-1.99 (2H, m), 3.11-3.72 (9H, m), 4.32-4.45 (2H, m ), 4.75 (1H, br s), 5.03 (1H, d, J = 10Hz), 6.22 (1H, d, J = 3.5Hz), 7.12 (2H, d, J = 8.5Hz), 7.31-7.43 (5H , m), 7.53-7.62 (2H, m), 7.71-7.75 (3H, m), 9.00 (1H, br s), 9.26 (1H, br s), 12.11 (1H, br s)
(-) ESI-MS (m / z): 571 (MH) -

（２２） ４’−［２−［［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−３−（イソプロピルチオ）−４−ビフェニルカルボキサミド塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.25 (6H, d, J=6.5Hz), 1.85-1.99 (2H, m), 2.96-3.27 (6H, m), 3.50-3.72 (5H, m), 4.75 (1H, br s), 4.99 (1H, d, J=10Hz), 6.35 (1H, d, J=4Hz), 7.34-7.52 (6H, m), 7.54-7.67 (2H, m), 7.67-7.81 (3H, m), 8.87 (1H, br s), 8.98 (1H, br s), 12.13 (1H, br s)
(-)ESI-MS (m/z): 589, 591 (M-H)- (22) 4 '-[2-[[(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] -N-[(3-hydroxypropyl) sulfonyl] -3- (isopropylthio) ) -4-Biphenylcarboxamide hydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 1.25 (6H, d, J = 6.5Hz), 1.85-1.99 (2H, m), 2.96-3.27 (6H, m), 3.50-3.72 (5H, m ), 4.75 (1H, br s), 4.99 (1H, d, J = 10Hz), 6.35 (1H, d, J = 4Hz), 7.34-7.52 (6H, m), 7.54-7.67 (2H, m), 7.67-7.81 (3H, m), 8.87 (1H, br s), 8.98 (1H, br s), 12.13 (1H, br s)
(-) ESI-MS (m / z): 589, 591 (MH) -

（２３） ３−（シクロヘキシルオキシ）−４’−［３−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］プロピル］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４−ビフェニルカルボキサミド塩酸塩
NMR (400 MHz, DMSO-d6, δ): 1.28-1.65 (6H, m), 1.67-1.79 (2H, m), 1.83-2.11 (6H, m), 2.72 (2H, t, J=7.60Hz), 2.94-3.04 (3H, m), 3.11-3.19 (1H, m), 3.47-3.59 (4H, m), 4.74 (1H, t, J=4.8Hz), 4.77-4.85 (1H, m), 4.93-5.0 (1H, m), 6.18 (1H, d, J=3.6Hz), 7.23-7.44 (9H, m), 7.67-7.76 (3H, m)
(-)ESI-MS (m/z): 593 (M-H)- (23) 3- (Cyclohexyloxy) -4 '-[3-[[(2R) -2-hydroxy-2-phenylethyl] amino] propyl] -N-[(3-hydroxypropyl) sulfonyl] -4- Biphenyl carboxamide hydrochloride
NMR (400 MHz, DMSO-d 6 , δ): 1.28-1.65 (6H, m), 1.67-1.79 (2H, m), 1.83-2.11 (6H, m), 2.72 (2H, t, J = 7.60Hz ), 2.94-3.04 (3H, m), 3.11-3.19 (1H, m), 3.47-3.59 (4H, m), 4.74 (1H, t, J = 4.8Hz), 4.77-4.85 (1H, m), 4.93-5.0 (1H, m), 6.18 (1H, d, J = 3.6Hz), 7.23-7.44 (9H, m), 7.67-7.76 (3H, m)
(-) ESI-MS (m / z): 593 (MH) -

（２４） ４’−［３−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］プロピル］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−３−イソプロポキシ−４−ビフェニルカルボキサミド塩酸塩
NMR (400 MHz, DMSO-d6, δ): 1.37 (6H, d, J=6.0Hz), 1.83-1.93 (2H, m), 1.95-2.09 (2H, m), 2.72 (2H, t, J=8.0Hz), 2.93-3.05 (3H, m), 3.10-3.19 (1H, m), 3.47-3.60 (4H, m), 4.75 (1H, t, J=5.20Hz), 4.91-5.03 (2H, m), 6.18 (1H, d, J=4Hz), 7.29=7.44 (9H, m), 7.67-7.73 (3H, m)
(-)ESI-MS (m/z): 553 (M-H)- (24) 4 '-[3-[[(2R) -2-hydroxy-2-phenylethyl] amino] propyl] -N-[(3-hydroxypropyl) sulfonyl] -3-isopropoxy-4-biphenylcarboxamide Hydrochloride
NMR (400 MHz, DMSO-d 6 , δ): 1.37 (6H, d, J = 6.0Hz), 1.83-1.93 (2H, m), 1.95-2.09 (2H, m), 2.72 (2H, t, J = 8.0Hz), 2.93-3.05 (3H, m), 3.10-3.19 (1H, m), 3.47-3.60 (4H, m), 4.75 (1H, t, J = 5.20Hz), 4.91-5.03 (2H, m), 6.18 (1H, d, J = 4Hz), 7.29 = 7.44 (9H, m), 7.67-7.73 (3H, m)
(-) ESI-MS (m / z): 553 (MH) -

（２５） ４’−［３−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］プロピル］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−３−イソブチル−４−ビフェニルカルボキサミド塩酸塩
NMR (400 MHz, DMSO-d6, δ): 0.87 (6H, d, J=6.4Hz), 1.79-1.93 (3H, m), 1.95-2.08 (2H, m), 2.65-2.77 (4H, m), 2.93-3.04 (3H, m), 3.09-3.19 (1H, m), 3.47-3.59 (4H, m), 4.70-4.82 (1H, m), 4.91-5.01 (1H, m), 6.14-6.21 (1H, m), 7.27-7.43 (7H, m), 7.50-7.69 (5H, m), 12.11 (1H, s)
(-)ESI-MS (m/z): 551 (M-H)- (25) 4 ′-[3-[[(2R) -2-hydroxy-2-phenylethyl] amino] propyl] -N-[(3-hydroxypropyl) sulfonyl] -3-isobutyl-4-biphenylcarboxamide hydrochloride salt
NMR (400 MHz, DMSO-d 6 , δ): 0.87 (6H, d, J = 6.4Hz), 1.79-1.93 (3H, m), 1.95-2.08 (2H, m), 2.65-2.77 (4H, m ), 2.93-3.04 (3H, m), 3.09-3.19 (1H, m), 3.47-3.59 (4H, m), 4.70-4.82 (1H, m), 4.91-5.01 (1H, m), 6.14-6.21 (1H, m), 7.27-7.43 (7H, m), 7.50-7.69 (5H, m), 12.11 (1H, s)
(-) ESI-MS (m / z): 551 (MH) -

（２６） ３−シクロペンチル−４’−［３−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］プロピル］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４−ビフェニルカルボキサミド塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.52-2.20 (12H, m), 2.71 (2H, t, J=7.53Hz), 2.87-3.29 (5H, m), 3.45-3.66 (4H, m), 4.69-4.86 (1H, m), 4.89-5.05 (1H, m), 6.18 (1H, d, J=4.02Hz), 7.25-7.70 (12H, m)
(-)ESI-MS (m/z): 563 (M-H)- (26) 3-cyclopentyl-4 ′-[3-[[(2R) -2-hydroxy-2-phenylethyl] amino] propyl] -N-[(3-hydroxypropyl) sulfonyl] -4-biphenylcarboxamide hydrochloride salt
NMR (200 MHz, DMSO-d 6 , δ): 1.52-2.20 (12H, m), 2.71 (2H, t, J = 7.53Hz), 2.87-3.29 (5H, m), 3.45-3.66 (4H, m ), 4.69-4.86 (1H, m), 4.89-5.05 (1H, m), 6.18 (1H, d, J = 4.02Hz), 7.25-7.70 (12H, m)
(-) ESI-MS (m / z): 563 (MH) -

（２７） ４’−［３−［［（２Ｒ）−２−（４−アミノフェニル）−２−ヒドロキシエチル］アミノ］プロピル］−３−（シクロヘキシルオキシ）−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４−ビフェニルカルボキサミド二塩酸塩
NMR (400 MHz, DMSO-d6, δ): 1.28-1.64 (6H, m), 1.67-1.79 (2H, m), 1.82-2.11 (6H, m), 2.72 (2H, t, J=7.6Hz), 2.89-3.19 (4H, m), 4.76-4.86 (1H, m), 4.95-5.04 (1H, m), 7.23-7.50 (8H, m), 7.65-7.78 (3H, m)
(-)ESI-MS (m/z): 608 (M-H)- (27) 4 '-[3-[[(2R) -2- (4-aminophenyl) -2-hydroxyethyl] amino] propyl] -3- (cyclohexyloxy) -N-[(3-hydroxypropyl) Sulfonyl] -4-biphenylcarboxamide dihydrochloride
NMR (400 MHz, DMSO-d 6 , δ): 1.28-1.64 (6H, m), 1.67-1.79 (2H, m), 1.82-2.11 (6H, m), 2.72 (2H, t, J = 7.6Hz ), 2.89-3.19 (4H, m), 4.76-4.86 (1H, m), 4.95-5.04 (1H, m), 7.23-7.50 (8H, m), 7.65-7.78 (3H, m)
(-) ESI-MS (m / z): 608 (MH) -

（２８） ４’−［３−［［（２Ｒ）−２−（４−アミノフェニル）−２−ヒドロキシエチル］アミノ］プロピル］−３−シクロペンチル−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４−ビフェニルカルボキサミド二塩酸塩
NMR (400 MHz, DMSO-d6, δ): 1.41-1.71 (4H, m), 1.75-1.93 (4H, m), 1.96-2.10 (4H, m), 2.71 (2H, t, J=7.32Hz), 2.92-3.04 (3H, m), 3.07-3.19 (1H, m), 3.26-3.36 (1H, m), 3.49-3.60 (4H, m), 4.95-5.01 (1H, m), 7.23-7.58 (8H, m), 7.60-7.71 (3H, m)
(-)ESI-MS (m/z): 578 (M-H)- (28) 4 '-[3-[[(2R) -2- (4-aminophenyl) -2-hydroxyethyl] amino] propyl] -3-cyclopentyl-N-[(3-hydroxypropyl) sulfonyl]- 4-biphenylcarboxamide dihydrochloride
NMR (400 MHz, DMSO-d 6 , δ): 1.41-1.71 (4H, m), 1.75-1.93 (4H, m), 1.96-2.10 (4H, m), 2.71 (2H, t, J = 7.32Hz ), 2.92-3.04 (3H, m), 3.07-3.19 (1H, m), 3.26-3.36 (1H, m), 3.49-3.60 (4H, m), 4.95-5.01 (1H, m), 7.23-7.58 (8H, m), 7.60-7.71 (3H, m)
(-) ESI-MS (m / z): 578 (MH) -

（２９） ４’−［３−［［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］プロピル］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−３−イソプロポキシ−４−ビフェニルカルボキサミド塩酸塩
NMR (400 MHz, DMSO-d6, δ): 1.37 (6H, d, J=5.9Hz), 1.84-1.93 (2H, m), 1.95-2.07 (2H, m), 2.72 (2H, t, J=7.5Hz), 2.91-3.07 (3H, m), 3.14-3.24 (1H, m), 3.49-3.58 (4H, m), 4.92-5.03 (2H, m), 6.33 (1H, br s), 7.32-7.52 (8H, m), 7.68-7.73 (3H, m), 11.21 (1H, s)
, t, J=7.5Hz), 2.91-3.07 (3h, m), 3.14-3.24 (1h, m), 3.49-3.58 (4H, m), 4.92-5.03 (2H, m), 6.33 (1H, br s), 7.32-7.52 (8H, m), 7.68-7.73 (3h, m), 11.21 (1H, s)
(-)ESI-MS (m/z): 587 (M-H)- (29) 4 '-[3-[[(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] propyl] -N-[(3-hydroxypropyl) sulfonyl] -3-isopropoxy- 4-biphenylcarboxamide hydrochloride
NMR (400 MHz, DMSO-d 6 , δ): 1.37 (6H, d, J = 5.9Hz), 1.84-1.93 (2H, m), 1.95-2.07 (2H, m), 2.72 (2H, t, J = 7.5Hz), 2.91-3.07 (3H, m), 3.14-3.24 (1H, m), 3.49-3.58 (4H, m), 4.92-5.03 (2H, m), 6.33 (1H, br s), 7.32 -7.52 (8H, m), 7.68-7.73 (3H, m), 11.21 (1H, s)
, t, J = 7.5Hz), 2.91-3.07 (3h, m), 3.14-3.24 (1h, m), 3.49-3.58 (4H, m), 4.92-5.03 (2H, m), 6.33 (1H, br s), 7.32-7.52 (8H, m), 7.68-7.73 (3h, m), 11.21 (1H, s)
(-) ESI-MS (m / z): 587 (MH) -

（３０） ３−（シクロヘキシルオキシ）−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４’−［３−［［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］プロピル］−４−ビフェニルカルボキサミド二塩酸塩
NMR (400 MHz, DMSO-d6, δ): 1.28-1.65 (6H, m), 1.67-1.79 (2H, m), 1.81-2.13 (6H, m), 2.73 (2H, t, J=7.68Hz), 2.90-3.05 (2H, m), 3.10-3.23 (1H, m), 3.27-3.38 (1H, m), 3.47-3.60 (4H, m), 4.76-4.86 (1H, m), 5.22-5.30 (1H, m), 7.32-7.44 (4H, m), 7.67-7.76 (3H, m), 7.91-7.98 (1H, m), 8.44 (1H, d, J=8.05Hz), 8.79-8.89 (2H, m), 11.2 (1H, s)
(-)ESI-MS (m/z): 594 (M-H)- (30) 3- (Cyclohexyloxy) -N-[(3-hydroxypropyl) sulfonyl] -4 ′-[3-[[(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] propyl ] -4-Biphenylcarboxamide dihydrochloride
NMR (400 MHz, DMSO-d 6 , δ): 1.28-1.65 (6H, m), 1.67-1.79 (2H, m), 1.81-2.13 (6H, m), 2.73 (2H, t, J = 7.68Hz ), 2.90-3.05 (2H, m), 3.10-3.23 (1H, m), 3.27-3.38 (1H, m), 3.47-3.60 (4H, m), 4.76-4.86 (1H, m), 5.22-5.30 (1H, m), 7.32-7.44 (4H, m), 7.67-7.76 (3H, m), 7.91-7.98 (1H, m), 8.44 (1H, d, J = 8.05Hz), 8.79-8.89 (2H , m), 11.2 (1H, s)
(-) ESI-MS (m / z): 594 (MH) -

（３１） Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４’−［３−［［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］プロピル］−３−イソブトキシ−４−ビフェニルカルボキサミド二塩酸塩
NMR (400 MHz, DMSO-d6, δ): 1.04 (6H, d, J=7Hz), 1.83-1.91 (2H, m), 1.99-2.13 (3H, m), 2.73 (2H, t, J=7.5Hz), 2.95-3.03 (2H, m), 3.12-3.22 (1H, m), 3.28-3.37 (1H, m), 3.47-3.58 (4H, m), 4.03 (2H, d, J=6.2Hz), 5.23-5.28 (1H, m), 7.33-7.39 (4H, m), 7.67-7.74 (3H, m), 7.91-7.97 (1H, m), 8.43 (1H, d, J=8Hz), 8.79-8.89 (2H, m), 11.21(1H, s)
(-)ESI-MS (m/z): 568 (M-H)- (31) N-[(3-hydroxypropyl) sulfonyl] -4 '-[3-[[(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] propyl] -3-isobutoxy-4 -Biphenylcarboxamide dihydrochloride
NMR (400 MHz, DMSO-d 6 , δ): 1.04 (6H, d, J = 7Hz), 1.83-1.91 (2H, m), 1.99-2.13 (3H, m), 2.73 (2H, t, J = 7.5Hz), 2.95-3.03 (2H, m), 3.12-3.22 (1H, m), 3.28-3.37 (1H, m), 3.47-3.58 (4H, m), 4.03 (2H, d, J = 6.2Hz ), 5.23-5.28 (1H, m), 7.33-7.39 (4H, m), 7.67-7.74 (3H, m), 7.91-7.97 (1H, m), 8.43 (1H, d, J = 8Hz), 8.79 -8.89 (2H, m), 11.21 (1H, s)
(-) ESI-MS (m / z): 568 (MH) -

（３２） Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４’−［３−［［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］プロピル］−３−イソプロポキシ−４−ビフェニルカルボキサミド二塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.37 (6H, d, J=6Hz), 1.81-2.11 (4H, m), 2.73 (2H, t, J=7.3Hz), 2.9-3.41 (4H, m), 3.46-3.61 (4H, m), 4.91-5.05 (1H, m), 5.19-5.31 (1H, m), 7.31-7.43 (4H, m), 7.66-7.76 (3H, m), 7.89-7.99 (1H, m), 8.44 (1H, d, J=8Hz), 8.78-8.89 (2H, m), 11.2 (1H, s)
(-)ESI-MS (m/z): 554 (M-H)- (32) N-[(3-hydroxypropyl) sulfonyl] -4 '-[3-[[(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] propyl] -3-isopropoxy- 4-biphenylcarboxamide dihydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 1.37 (6H, d, J = 6Hz), 1.81-2.11 (4H, m), 2.73 (2H, t, J = 7.3Hz), 2.9-3.41 (4H , m), 3.46-3.61 (4H, m), 4.91-5.05 (1H, m), 5.19-5.31 (1H, m), 7.31-7.43 (4H, m), 7.66-7.76 (3H, m), 7.89 -7.99 (1H, m), 8.44 (1H, d, J = 8Hz), 8.78-8.89 (2H, m), 11.2 (1H, s)
(-) ESI-MS (m / z): 554 (MH) -

実施例６
酢酸３−［［［［４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（６−クロロ−３−ピリジル）−２−ヒドロキシエチル］アミノ］エトキシ］−３−（シクロヘキシルオキシ）−４−ビフェニリル］カルボニル］アミノ］スルホニル］プロピル（３１１ｍｇ）、１０％パラジウム活性炭（５０％湿潤、６２ｍｇ）、蟻酸アンモニウム（２５３ｍｇ）、メタノール（６．２ｍｌ）と水（６．２ｍｌ）の混合物を３時間還流した。室温まで冷却後、触媒を濾去し、メタノールで洗浄した。濾液を真空濃縮し、残留物をシリカゲルクロマトグラフィー（溶離溶媒：ヘキサン／酢酸エチル）に付して、酢酸３−［［［［４’−［２−（第三級ブトキシカルボニル）［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エトキシ］−３−（シクロヘキシルオキシ）−４−ビフェニリル］カルボニル］アミノ］スルホニル］プロピル（１５６ｍｇ）を白色固形物として得た。
(-)ESI-MS (m/z): 738 (M-H)- Example 6
Acetic acid 3-[[[[4 '-[2-[(tertiary butoxycarbonyl) [(2R) -2- (6-chloro-3-pyridyl) -2-hydroxyethyl] amino] ethoxy] -3- (Cyclohexyloxy) -4-biphenylyl] carbonyl] amino] sulfonyl] propyl (311 mg), 10% palladium on activated carbon (50% wet, 62 mg), ammonium formate (253 mg), methanol (6.2 ml) and water (6.2 ml) ) Was refluxed for 3 hours. After cooling to room temperature, the catalyst was filtered off and washed with methanol. The filtrate was concentrated in vacuo, and the residue was subjected to silica gel chromatography (eluent: hexane / ethyl acetate) to give acetic acid 3-[[[[4 '-[2- (tertiary butoxycarbonyl) [(2R) 2-Hydroxy-2- (3-pyridyl) ethyl] amino] ethoxy] -3- (cyclohexyloxy) -4-biphenylyl] carbonyl] amino] sulfonyl] propyl (156 mg) was obtained as a white solid.
(-) ESI-MS (m / z): 738 (MH) -

実施例７
酢酸３−［［［［４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エトキシ］−３−（シクロヘキシルオキシ）−４−ビフェニリル］カルボニル］アミノ］スルホニル］プロピル（１５２ｍｇ）のメタノール（１．５２ｍｌ）とテトラヒドロフラン（０．７６ｍｌ）中の溶液に、１Ｎ水酸化ナトリウム（０．６１６ｍｌ）を加え、混合物を室温で４時間攪拌した。１Ｎ塩酸（０．６１６ｍｌ）を加えて混合物の反応を停止させ、溶媒を真空濃縮した。残留固形物をクロロホルム／メタノール（４／１、１０ｍｌ）に溶解し、硫酸マグネシウムで乾燥した。濾過後、溶媒を留去して白色固形物（１６１ｍｇ）を得て、これをシリカゲルクロマトグラフィー（溶離溶媒：ヘキサン／酢酸エチル）に付して、［２−［［３’−（シクロヘキシルオキシ）−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］オキシ］エチル］［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］カルバミン酸第三級ブチル（１３５ｍｇ）を白色固形物として得た。
(-)ESI-MS (m/z): 696 (M-H)- Example 7
Acetic acid 3-[[[[4 '-[2-[(tertiarybutoxycarbonyl) [(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] ethoxy] -3- (cyclohexyloxy) To a solution of -4-biphenylyl] carbonyl] amino] sulfonyl] propyl (152 mg) in methanol (1.52 ml) and tetrahydrofuran (0.76 ml) was added 1N sodium hydroxide (0.616 ml) and the mixture was at room temperature. Stir for 4 hours. 1N hydrochloric acid (0.616 ml) was added to quench the mixture and the solvent was concentrated in vacuo. The residual solid was dissolved in chloroform / methanol (4/1, 10 ml) and dried over magnesium sulfate. After filtration, the solvent was distilled off to obtain a white solid (161 mg), which was subjected to silica gel chromatography (eluent: hexane / ethyl acetate) to give [2-[[3 ′-(cyclohexyloxy)]. -4 ′-[[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -4-biphenylyl] oxy] ethyl] [(2R) -2-hydroxy-2- (3-pyridyl) ethyl] carbamic acid Grade butyl (135 mg) was obtained as a white solid.
(-) ESI-MS (m / z): 696 (MH) -

実施例８
［２−［３’−（シクロヘキシルオキシ）−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］エチル］［（２Ｒ）−２−ヒドロキシ−２−（４−ニトロフェニル）エチル］カルバミン酸第三級ブチル（２３４ｍｇ）、鉄粉末（５４ｍｇ）、塩化アンモニウム（８．６ｍｇ）、エタノール（３．５１ｍｌ）と水（１．１７ｍｌ）の混合物を５０分間還流した。室温まで冷却後、混合物をセライトパッドで濾過し、酢酸エチル（２０ｍｌ）で洗浄した。濾液を食塩水（２０ｍｌ）で洗浄し、硫酸マグネシウムで乾燥した。濾過後、溶媒を留去して、粗製生成物（２１７ｍｇ）を得て、これをシリカゲルクロマトグラフィー（溶離溶媒：ヘキサン／酢酸エチル＝１／２〜１／３）に付して、［（２Ｒ）−２−（４−アミノフェニル）−２−ヒドロキシエチル］［２−［３’−（シクロヘキシルオキシ）−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］エチル］カルバミン酸第三級ブチル（１３６ｍｇ）を黄色固形物として得た。
(-)ESI-MS (m/z): 694 (M-H)- Example 8
[2- [3 ′-(cyclohexyloxy) -4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -4-biphenylyl] ethyl] [(2R) -2-hydroxy-2- (4 -Nitrophenyl) ethyl] tertiary butyl carbamate (234 mg), iron powder (54 mg), ammonium chloride (8.6 mg), a mixture of ethanol (3.51 ml) and water (1.17 ml) was refluxed for 50 minutes. . After cooling to room temperature, the mixture was filtered through a celite pad and washed with ethyl acetate (20 ml). The filtrate was washed with brine (20 ml) and dried over magnesium sulfate. After filtration, the solvent was distilled off to obtain a crude product (217 mg), which was subjected to silica gel chromatography (eluent: hexane / ethyl acetate = 1/2 to 1/3) to give [(2R ) -2- (4-Aminophenyl) -2-hydroxyethyl] [2- [3 ′-(cyclohexyloxy) -4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -4-biphenylyl Ethyl] Certiary butyl carbamate (136 mg) was obtained as a yellow solid.
(-) ESI-MS (m / z): 694 (MH) -

実施例９
下記の化合物を実施例８と同様の方法にしたがって得た。
（１） ［（２Ｒ）−２−（４−アミノフェニル）−２−ヒドロキシエチル］［２−［４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−３’−イソブチル−４−ビフェニリル］エチル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 652 (M-H)- Example 9
The following compound was obtained according to the same method as in Example 8.
(1) [(2R) -2- (4-aminophenyl) -2-hydroxyethyl] [2- [4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -3′-isobutyl- 4-Biphenylyl] ethyl] tertiary butyl carbamate
(-) ESI-MS (m / z): 652 (MH) -

（２） ［（２Ｒ）−２−（４−アミノフェニル）−２−ヒドロキシエチル］［２−［３’−シクロペンチル−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］エチル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 664 (M-H)- (2) [(2R) -2- (4-aminophenyl) -2-hydroxyethyl] [2- [3′-cyclopentyl-4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl]- 4-Biphenylyl] ethyl] tertiary butyl carbamate
(-) ESI-MS (m / z): 664 (MH) -

（３） ［（２Ｒ）−２−（４−アミノフェニル）−２−ヒドロキシエチル］［２−［［３’−（シクロヘキシルオキシ）−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］オキシ］エチル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 710 (M-H)- (3) [(2R) -2- (4-Aminophenyl) -2-hydroxyethyl] [2-[[3 ′-(cyclohexyloxy) -4 ′-[[[(3-hydroxypropyl) sulfonyl] amino ] Carbonyl] -4-biphenylyl] oxy] ethyl] tertiary butyl carbamate
(-) ESI-MS (m / z): 710 (MH) -

（４） ［（２Ｒ）−２−（４−アミノフェニル）−２−ヒドロキシエチル］［２−［［３’−シクロペンチル−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］オキシ］エチル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 680 (M-H)- (4) [(2R) -2- (4-aminophenyl) -2-hydroxyethyl] [2-[[3′-cyclopentyl-4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -4-biphenylyl] oxy] ethyl] tertiary butyl carbamate
(-) ESI-MS (m / z): 680 (MH) -

（５） ［（２Ｒ）−２−（３−アミノフェニル）−２−ヒドロキシエチル］［２−［３’−（シクロヘキシルオキシ）−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］エチル］カルバミン酸第三級ブチル (5) [(2R) -2- (3-aminophenyl) -2-hydroxyethyl] [2- [3 ′-(cyclohexyloxy) -4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] Carbonyl] -4-biphenylyl] ethyl] tertiary butyl carbamate

（６） ［（２Ｒ）−２−（４−アミノフェニル）−２−ヒドロキシエチル］［３−［３’−（シクロヘキシルオキシ）−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］プロピル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 708 (M-H)- (6) [(2R) -2- (4-aminophenyl) -2-hydroxyethyl] [3- [3 ′-(cyclohexyloxy) -4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] Carbonyl] -4-biphenylyl] propyl] tertiary butyl carbamate
(-) ESI-MS (m / z): 708 (MH) -

（７） ［（２Ｒ）−２−（４−アミノフェニル）−２−ヒドロキシエチル］［３−［３’−シクロペンチル−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］プロピル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 678 (M-H)- (7) [(2R) -2- (4-aminophenyl) -2-hydroxyethyl] [3- [3'-cyclopentyl-4 '-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl]- 4-Biphenylyl] propyl] tertiary butyl carbamate
(-) ESI-MS (m / z): 678 (MH) -

実施例１０
［２−［４’−［［［［２−（ベンジルオキシ）エチル］スルホニル］アミノ］カルボニル］−３’−（シクロヘキシルオキシ）−４−ビフェニリル］エチル］［（２Ｒ）−２−ヒドロキシ−２−（４−ニトロフェニル）エチル］カルバミン酸第三級ブチル（２１５ｍｇ）、１０％パラジウム活性炭（５０％湿潤、６４５ｍｇ）、蟻酸アンモニウム（８４５ｍｇ）、メタノール（６．４５ｍｌ）と水（０．６５ｍｌ）の混合物を２０分間還流した。室温まで冷却後、触媒を濾去し、メタノールで洗浄した。濾液を真空濃縮し、残留物をシリカゲルクロマトグラフィー（溶離溶媒：ヘキサン／酢酸エチル）に付して、［（２Ｒ）−２−（４−アミノフェニル）−２−ヒドロキシエチル］［２−［３’−（シクロヘキシルオキシ）−４’−［［［（２−ヒドロキシエチル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］エチル］カルバミン酸第三級ブチル（１２３ｍｇ）を淡黄色固形物として得た。
(-)ESI-MS (m/z): 680 (M-H)- Example 10
[2- [4 ′-[[[[2- (Benzyloxy) ethyl] sulfonyl] amino] carbonyl] -3 ′-(cyclohexyloxy) -4-biphenylyl] ethyl] [(2R) -2-hydroxy-2 -(4-Nitrophenyl) ethyl] tertiary butyl carbamate (215 mg), 10% palladium on activated carbon (50% wet, 645 mg), ammonium formate (845 mg), methanol (6.45 ml) and water (0.65 ml) Was refluxed for 20 minutes. After cooling to room temperature, the catalyst was filtered off and washed with methanol. The filtrate was concentrated in vacuo and the residue was subjected to silica gel chromatography (eluent: hexane / ethyl acetate) to give [(2R) -2- (4-aminophenyl) -2-hydroxyethyl] [2- [3 '-(Cyclohexyloxy) -4'-[[[(2-hydroxyethyl) sulfonyl] amino] carbonyl] -4-biphenylyl] ethyl] tertiary butyl carbamate (123 mg) was obtained as a pale yellow solid.
(-) ESI-MS (m / z): 680 (MH) -

実施例１１
４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エチル］−３−（シクロヘプチルオキシ）−４−ビフェニルカルボン酸（４５７ｍｇ）のＮ，Ｎ−ジメチルホルムアミド（４．６ｍｌ）中の溶液に、Ｎ，Ｎ’−カルボニルジイミダゾール（１５５ｍｇ）を加え、混合物を室温で１時間攪拌した。混合物に酢酸３−（アミノスルホニル）プロピル（１７３ｍｇ）と１，８−ジアザビシクロ［５．４．０］ウンデク−７−エン（０．１４３ｍｌ）を加え、混合物を１２０℃で２４時間攪拌した。室温まで冷却後、ｐＨ６．８６緩衝液（２０ｍｌ）を加えて混合物の反応を停止させ、酢酸エチル（２０ｍｌ×２）で抽出した。合わせた抽出物をｐＨ６．８６緩衝液（４０ｍｌ×２）と食塩水（４０ｍｌ）で洗浄し、硫酸マグネシウムで乾燥した。濾過後、溶媒を留去して、黄色固形物（４８６ｍｇ）を得て、これをシリカゲルクロマトグラフィー（ヘキサン／酢酸エチル）に付して、酢酸３−［［［［４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エチル］−３−（シクロヘプチルオキシ）−４−ビフェニリル］カルボニル］アミノ］スルホニル］プロピル（２７６ｍｇ）を淡黄色固形物として得た。
(-)ESI-MS (m/z): 736 (M-H)- Example 11
4 ′-[2-[(Tertiary butoxycarbonyl) [(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] ethyl] -3- (cycloheptyloxy) -4-biphenylcarboxylic acid To a solution of (457 mg) in N, N-dimethylformamide (4.6 ml) was added N, N′-carbonyldiimidazole (155 mg) and the mixture was stirred at room temperature for 1 hour. To the mixture was added 3- (aminosulfonyl) propyl acetate (173 mg) and 1,8-diazabicyclo [5.4.0] undec-7-ene (0.143 ml), and the mixture was stirred at 120 ° C. for 24 hours. After cooling to room temperature, the pH of 6.86 buffer (20 ml) was added to stop the reaction of the mixture, and the mixture was extracted with ethyl acetate (20 ml × 2). The combined extracts were washed with pH 6.86 buffer (40 ml × 2) and brine (40 ml) and dried over magnesium sulfate. After filtration, the solvent was distilled off to give a yellow solid (486 mg), which was subjected to silica gel chromatography (hexane / ethyl acetate) to give acetic acid 3-[[[[4 ′-[2- [ (Tertiary butoxycarbonyl) [(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] ethyl] -3- (cycloheptyloxy) -4-biphenylyl] carbonyl] amino] sulfonyl] propyl ( 276 mg) as a pale yellow solid.
(-) ESI-MS (m / z): 736 (MH) -

実施例１２
下記の化合物を実施例７と同様の方法にしたがって得た。 Example 12
The following compound was obtained according to the same method as in Example 7.

［２−［３’−（シクロヘプチルオキシ）−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］エチル］［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 694 (M-H)- [2- [3 ′-(Cycloheptyloxy) -4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -4-biphenylyl] ethyl] [(2R) -2-hydroxy-2- ( 3-Pyridyl) ethyl] tertiary butyl carbamate
(-) ESI-MS (m / z): 694 (MH) -

実施例１３
４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（６−クロロ−３−ピリジル）−２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニルカルボン酸（１８０ｍｇ）のＮ，Ｎ−ジメチルホルムアミド（１ｍｌ）中の溶液に、酢酸２−（アミノスルホニル）エチル（２０５ｍｇ）、Ｎ，Ｎ−ジメチルアミノピリジン（６５ｍｇ）と１−［３−（ジメチルアミノ）プロピル］−３−エチルカルボジイミド塩酸塩（６１ｍｇ）を室温で加え、混合物を同温で４日間攪拌した。混合物を０．５Ｎ塩酸に注ぎ、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸ナトリウムで乾燥後、溶媒を減圧留去して、アシルスルホンアミド生成物を得た。上記の生成物のメタノール（３ｍｌ）中の溶液に、４−メチルベンゼンスルホン酸（３０ｍｇ）を室温で加え、混合物を同温で一夜攪拌した。混合物を酢酸エチルと水の混合物に注いだ。有機層を分離し、食塩水で洗浄し、硫酸ナトリウムで乾燥後、溶媒を減圧留去した。残留物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝９５／５）で精製して、［（２Ｒ）−２−（６−クロロ−３−ピリジル）−２−ヒドロキシエチル］［２−［３’−（シクロヘキシルオキシ）−４’−［［［（２−ヒドロキシエチル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］エチル］カルバミン酸第三級ブチル（４９ｍｇ）を得た。
(+)ESI-MS (m/z): 724 (M+Na)+ Example 13
4 ′-[2-[(Tertiary butoxycarbonyl) [(2R) -2- (6-chloro-3-pyridyl) -2- (tetrahydro-2H-pyran-2-yloxy) ethyl] amino] ethyl] To a solution of -3- (cyclohexyloxy) -4-biphenylcarboxylic acid (180 mg) in N, N-dimethylformamide (1 ml) was added 2- (aminosulfonyl) ethyl acetate (205 mg), N, N-dimethylaminopyridine. (65 mg) and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (61 mg) were added at room temperature, and the mixture was stirred at the same temperature for 4 days. The mixture was poured into 0.5N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain an acylsulfonamide product. To a solution of the above product in methanol (3 ml), 4-methylbenzenesulfonic acid (30 mg) was added at room temperature and the mixture was stirred at the same temperature overnight. The mixture was poured into a mixture of ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 95/5) to give [(2R) -2- (6-chloro-3-pyridyl) -2-hydroxyethyl] [2- [3′- (Cyclohexyloxy) -4 ′-[[[(2-hydroxyethyl) sulfonyl] amino] carbonyl] -4-biphenylyl] ethyl] tertiary butyl carbamate (49 mg) was obtained.
(+) ESI-MS (m / z): 724 (M + Na) +

実施例１４
下記の化合物を実施例６と同様の方法にしたがって得た。 Example 14
The following compound was obtained according to the same method as in Example 6.

［２−［３’−（シクロヘキシルオキシ）−４’−［［［（２−ヒドロキシエチル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］エチル］［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］カルバミン酸第三級ブチル
(+)ESI-MS (m/z): 668 (M+H)+ [2- [3 ′-(cyclohexyloxy) -4 ′-[[[(2-hydroxyethyl) sulfonyl] amino] carbonyl] -4-biphenylyl] ethyl] [(2R) -2-hydroxy-2- (3 -Pyridyl) ethyl] tertiary butyl carbamate
(+) ESI-MS (m / z): 668 (M + H) +

実施例１５
［２−（４−ブロモフェニル）エチル］［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］カルバミン酸第三級ブチル（３３１ｍｇ）の１，４−ジオキサン（３．３ｍｌ）中の溶液に、［４−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−３−イソプロポキシフェニル］ホウ素酸（３２５ｍｇ）、テトラキス（トリフェニルホスフィン）パラジウム（９１ｍｇ）と炭酸ナトリウム水溶液（２Ｍ、１．４ｍｌ）を加え、混合物を窒素雰囲気下に８０℃で３時間攪拌した。混合物を酢酸エチルと水の混合物に注いだ。有機層を分離し、食塩水で洗浄し、硫酸ナトリウムで乾燥後、溶媒を減圧留去した。残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール＝１００／３）で精製して、［２−［４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−３’−イソプロポキシ−４−ビフェニリル］エチル］［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］カルバミン酸第三級ブチル（１０８ｍｇ）を得た。
(+)ESI-MS (m/z): 664 (M+Na)+ Example 15
[2- (4-Bromophenyl) ethyl] [(2R) -2-hydroxy-2- (3-pyridyl) ethyl] tertiary butyl carbamate (331 mg) in 1,4-dioxane (3.3 ml) [4-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -3-isopropoxyphenyl] boronic acid (325 mg), tetrakis (triphenylphosphine) palladium (91 mg) and an aqueous sodium carbonate solution ( 2M, 1.4 ml) was added and the mixture was stirred at 80 ° C. for 3 hours under nitrogen atmosphere. The mixture was poured into a mixture of ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol = 100/3) to give [2- [4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -3′-isopropoxy. -4-Biphenylyl] ethyl] [(2R) -2-hydroxy-2- (3-pyridyl) ethyl] tertiary butyl carbamate (108 mg) was obtained.
(+) ESI-MS (m / z): 664 (M + Na) +

実施例１６
下記の化合物を実施例１１と同様の方法にしたがって得た。
（１） ［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］［２−［４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−３’−イソブトキシ−４−ビフェニリル］エチル］カルバミン酸第三級ブチル
(+)ESI-MS (m/z): 677 (M+Na)+ Example 16
The following compound was obtained according to the same method as in Example 11.
(1) [(2R) -2-hydroxy-2-phenylethyl] [2- [4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -3′-isobutoxy-4-biphenylyl] ethyl ] Tertiary butyl carbamate
(+) ESI-MS (m / z): 677 (M + Na) +

（２） ［２−［３’−シクロペンチル−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］エチル］［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］カルバミン酸第三級ブチル
(+)ESI-MS (m/z): 673 (M+Na)+ (2) [2- [3′-Cyclopentyl-4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -4-biphenylyl] ethyl] [(2R) -2-hydroxy-2-phenylethyl ] Tertiary butyl carbamate
(+) ESI-MS (m / z): 673 (M + Na) +

（３） 酢酸３−［［［［４’−［３−［（第三級ブトキシカルボニル）［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］プロピル］−３−イソブトキシ−４−ビフェニリル］カルボニル］アミノ］スルホニル］プロピル
(-)ESI-MS (m/z): 710 (M-H)- (3) Acetic acid 3-[[[[[4 '-[3-[(tertiary butoxycarbonyl) [(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] propyl] -3-isobutoxy -4-biphenylyl] carbonyl] amino] sulfonyl] propyl
(-) ESI-MS (m / z): 710 (MH)-

（４） 酢酸３−［［［［４’−［３−［（第三級ブトキシカルボニル）［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］プロピル］−３−イソプロポキシ−４−ビフェニリル］カルボニル］アミノ］スルホニル］プロピル
(-)ESI-MS (m/z): 696 (M-H)- (4) Acetic acid 3-[[[[4 '-[3-[(tertiary butoxycarbonyl) [(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] propyl] -3-iso Propoxy-4-biphenylyl] carbonyl] amino] sulfonyl] propyl
(-) ESI-MS (m / z): 696 (MH) -

（５） ３−［［［［４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニリル］カルボニル］アミノ］スルホニル］プロパン酸メチル
(-)ESI-MS (m/z): 707 (M-H)- (5) 3-[[[[4 '-[2-[(Tertiary butoxycarbonyl) [(2R) -2-hydroxy-2-phenylethyl] amino] ethyl] -3- (cyclohexyloxy) -4 -Biphenylyl] carbonyl] amino] sulfonyl] propanoic acid methyl ester
(-) ESI-MS (m / z): 707 (MH) -

（６） 酢酸４−［［［［４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニリル］カルボニル］アミノ］スルホニル］ブチル
(-)ESI-MS (m/z): 735 (M-H)- (6) Acetic acid 4-[[[[4 '-[2-[(tertiary butoxycarbonyl) [(2R) -2-hydroxy-2-phenylethyl] amino] ethyl] -3- (cyclohexyloxy)- 4-biphenylyl] carbonyl] amino] sulfonyl] butyl
(-) ESI-MS (m / z): 735 (MH) -

実施例１７
下記の化合物を実施例１３と同様の方法にしたがって得た。
（１） ［２−［３’−（シクロヘキシルオキシ）−４’−［［［（２−ヒドロキシエチル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］エチル］［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］カルバミン酸第三級ブチル
(+)ESI-MS (m/z): 689 (M+Na)+ Example 17
The following compound was obtained in the same manner as in Example 13.
(1) [2- [3 ′-(Cyclohexyloxy) -4 ′-[[[(2-hydroxyethyl) sulfonyl] amino] carbonyl] -4-biphenylyl] ethyl] [(2R) -2-hydroxy-2 -Phenylethyl] tertiary butyl carbamate
(+) ESI-MS (m / z): 689 (M + Na) +

（２） ［２−［３’−（シクロヘキシルオキシ）−４’−［［［（２−ヒドロキシエチル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］エチル］［（１Ｓ，２Ｒ）−２−ヒドロキシ−１−メチル−２−フェニルエチル］カルバミン酸第三級ブチル
(+)ESI-MS (m/z): 703 (M+Na)+ (2) [2- [3 ′-(cyclohexyloxy) -4 ′-[[[(2-hydroxyethyl) sulfonyl] amino] carbonyl] -4-biphenylyl] ethyl] [(1S, 2R) -2-hydroxy -1-methyl-2-phenylethyl] tertiary butyl carbamate
(+) ESI-MS (m / z): 703 (M + Na) +

実施例１８
［２−［４’−（アミノスルホニル）−３’−（シクロヘキシルオキシ）−４−ビフェニリル］エチル］［（２Ｒ）−２−フェニル−２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エチル］カルバミン酸第三級ブチル（１８８ｍｇ）のＮ，Ｎ−ジメチルホルムアミド（１ｍｌ）中の溶液に、４−［（第三級ブトキシカルボニル）アミノ］ブタン酸（１４６ｍｇ）、Ｎ，Ｎ−ジメチルアミノピリジン（４０．６ｍｇ）と１−［３−（ジメチルアミノ）プロピル］−３−エチルカルボジイミド塩酸塩（１４９ｍｇ）を室温で加え、混合物を同温で３日間攪拌した。混合物を酢酸エチルで希釈し、重炭酸ナトリウム水溶液、０．１Ｎ塩酸と食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥後、溶媒を減圧留去して、アシルスルホンアミド生成物を得た。生成物のメタノール（３ｍｌ）中の溶液に、４−メチルベンゼンスルホン酸（３６ｍｇ）を室温で加え、混合物を同温で２日間攪拌した。混合物を酢酸エチルで希釈し、水と食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥後、溶媒を減圧留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝６／４）で精製して、［２−［４’−［［［４−［（第三級ブトキシカルボニル）アミノ］ブタノイル］アミノ］スルホニル］−３’−（シクロヘキシルオキシ）−４−ビフェニリル］エチル］［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］カルバミン酸第三級ブチル（１１７ｍｇ）を得た。
(+)ESI-MS (m/z): 802 (M+Na)+ Example 18
[2- [4 ′-(aminosulfonyl) -3 ′-(cyclohexyloxy) -4-biphenylyl] ethyl] [(2R) -2-phenyl-2- (tetrahydro-2H-pyran-2-yloxy) ethyl] To a solution of tertiary butyl carbamate (188 mg) in N, N-dimethylformamide (1 ml) was added 4-[(tertiarybutoxycarbonyl) amino] butanoic acid (146 mg), N, N-dimethylaminopyridine ( 40.6 mg) and 1- [3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (149 mg) were added at room temperature, and the mixture was stirred at the same temperature for 3 days. The mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate, 0.1N hydrochloric acid and brine. The organic layer was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain an acylsulfonamide product. To a solution of the product in methanol (3 ml) 4-methylbenzenesulfonic acid (36 mg) was added at room temperature and the mixture was stirred at the same temperature for 2 days. The mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/4) to obtain [2- [4 ′-[[[4-[(tertiarybutoxycarbonyl) amino] butanoyl] amino] sulfonyl]. -3 ′-(cyclohexyloxy) -4-biphenylyl] ethyl] [(2R) -2-hydroxy-2-phenylethyl] carbamate tertiary butyl (117 mg) was obtained.
(+) ESI-MS (m / z): 802 (M + Na) +

実施例１９
［２−［４’−［［［４−［（第三級ブトキシカルボニル）アミノ］ブタノイル］アミノ］スルホニル］−３’−（シクロヘキシルオキシ）−４−ビフェニリル］エチル］［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］カルバミン酸第三級ブチル（１１０ｍｇ）の酢酸エチル（１ｍｌ）中の溶液に、塩化水素／酢酸エチル（４Ｎ、１ｍｌ）を室温で加え、混合物を同温で６時間攪拌した。混合物を濾過して沈殿物を採取し、沈殿物を酢酸エチル／ヘキサン（１：１）で洗浄した。沈殿物を減圧乾燥して、４−アミノ−Ｎ−［［３−（シクロヘキシルオキシ）−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エチル］−４−ビフェニリル］スルホニル］ブタンアミド二塩酸塩（８５ｍｇ）を得た。
NMR (200 MHz, DMSO-d6, δ): 1.25-1.98 (12H, m), 2.36 (2H, t, J=7.3Hz), 2.64-2.77 (2H, m), 2.99-3.28 (6H, m), 4.76-4.85 (1H, m), 4.97-5.07 (1H, m), 6.24 (1H, d, J=4.0Hz), 7.3-7.43 (9H, m), 7.73 (2H, d, J=8.5Hz), 7.88 (1H, d, J=8.0Hz), 7.98 (2H, br s), 8.98 (1H, br s), 9.41 (1H, br s), 11.94 (1H, br s)
(-)ESI-MS (m/z): 578 (M-H)- Example 19
[2- [4 '-[[[4-[(Tertiarybutoxycarbonyl) amino] butanoyl] amino] sulfonyl] -3'-(cyclohexyloxy) -4-biphenylyl] ethyl] [(2R) -2- Hydroxy-2-phenylethyl] tert-butyl carbamate (110 mg) in ethyl acetate (1 ml) was added hydrogen chloride / ethyl acetate (4N, 1 ml) at room temperature and the mixture was stirred at the same temperature for 6 hours. did. The mixture was filtered to collect the precipitate, which was washed with ethyl acetate / hexane (1: 1). The precipitate was dried under reduced pressure to give 4-amino-N-[[3- (cyclohexyloxy) -4 ′-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethyl] -4. -Biphenylyl] sulfonyl] butanamide dihydrochloride (85 mg) was obtained.
NMR (200 MHz, DMSO-d 6 , δ): 1.25-1.98 (12H, m), 2.36 (2H, t, J = 7.3Hz), 2.64-2.77 (2H, m), 2.99-3.28 (6H, m ), 4.76-4.85 (1H, m), 4.97-5.07 (1H, m), 6.24 (1H, d, J = 4.0Hz), 7.3-7.43 (9H, m), 7.73 (2H, d, J = 8.5 Hz), 7.88 (1H, d, J = 8.0Hz), 7.98 (2H, br s), 8.98 (1H, br s), 9.41 (1H, br s), 11.94 (1H, br s)
(-) ESI-MS (m / z): 578 (MH) -

実施例２０
下記の化合物を実施例１８と同様の方法にしたがって得た。 Example 20
The following compound was obtained according to the same method as in Example 18.

［２−［４’−［［［［（第三級ブトキシカルボニル）アミノ］アセチル］アミノ］スルホニル］−３’−（シクロヘキシルオキシ）−４−ビフェニリル］エチル］［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］カルバミン酸第三級ブチル
(+)ESI-MS (m/z): 774 (M+Na)+ [2- [4 ′-[[[[(Tertiary butoxycarbonyl) amino] acetyl] amino] sulfonyl] -3 ′-(cyclohexyloxy) -4-biphenylyl] ethyl] [(2R) -2-hydroxy- 2-Phenylethyl] tertiary butyl carbamate
(+) ESI-MS (m / z): 774 (M + Na) +

実施例２１
下記の化合物を実施例１９と同様の方法にしたがって得た。
（１） ２−アミノ−Ｎ−［［３−（シクロヘキシルオキシ）−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エチル］−４−ビフェニリル］スルホニル］アセトアミド二塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.24-1.98 (10H, m), 2.99-3.28 (6H, m), 3.65 (2H, br s), 4.74-4.87 (1H, m), 4.99-5.08 (1H, m), 6.25 (1H, br s), 7.3-7.45 (9H, m), 7.72 (2H, d, J=8.0Hz), 7.93 (1H, d, J=8.5Hz), 8.26 (3H, br s), 8.99 (1H, br s), 9.51 (1H, br s), 12.52 (1H, br s)
(-)ESI-MS (m/z): 550 (M-H)- Example 21
The following compound was obtained in the same manner as in Example 19.
(1) 2-Amino-N-[[3- (cyclohexyloxy) -4 ′-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethyl] -4-biphenylyl] sulfonyl] Acetamide dihydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 1.24-1.98 (10H, m), 2.99-3.28 (6H, m), 3.65 (2H, br s), 4.74-4.87 (1H, m), 4.99- 5.08 (1H, m), 6.25 (1H, br s), 7.3-7.45 (9H, m), 7.72 (2H, d, J = 8.0Hz), 7.93 (1H, d, J = 8.5Hz), 8.26 ( 3H, br s), 8.99 (1H, br s), 9.51 (1H, br s), 12.52 (1H, br s)
(-) ESI-MS (m / z): 550 (MH) -

（２） ３−［［［［３−（シクロヘキシルオキシ）−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エチル］−４−ビフェニリル］カルボニル］アミノ］スルホニル］プロパン酸塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.2-2.2 (10H, m), 2.74 (2H, t, J=7.2Hz), 3.0-3.4 (6H, m), 3.75 (1H, t, J=7.2Hz), 4.7-4.85 (1H, m), 4.9-5.0 (1H, m), 6.22 (1H, d, J=3.6Hz), 7.3-7.4 (10H, m), 7.72 (2H, dd, J=2.1, 8.1Hz) (2) 3-[[[[[3- (Cyclohexyloxy) -4 ′-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethyl] -4-biphenylyl] carbonyl] amino] Sulfonyl] propanoic acid hydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 1.2-2.2 (10H, m), 2.74 (2H, t, J = 7.2Hz), 3.0-3.4 (6H, m), 3.75 (1H, t, J = 7.2Hz), 4.7-4.85 (1H, m), 4.9-5.0 (1H, m), 6.22 (1H, d, J = 3.6Hz), 7.3-7.4 (10H, m), 7.72 (2H, dd, (J = 2.1, 8.1Hz)

（３） ３−（シクロヘキシルオキシ）−Ｎ−［（３−ヒドロキシ−３−メチルブチル）スルホニル］−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エチル］−４−ビフェニルカルボキサミド塩酸塩
NMR (400 MHz, DMSO-d6, δ): 1.11 (1H, s), 1.12-2.0 (12H, m), 2.98-3.06 (2H, m), 3.15-3.42 (6H, m), 3.51-3.57 (2H, m), 4.55 (1H, s), 4.75-4.82 (1H, m), 4.91-4.94 (1H, m), 6.21 (1H, d, J=1.7Hz), 7.3-7.42 (10H, m), 7.73 (2H, d, J=4.1Hz)
(-)ESI-MS (m/z): 607 (M-H)- (3) 3- (Cyclohexyloxy) -N-[(3-hydroxy-3-methylbutyl) sulfonyl] -4 ′-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethyl] -4-biphenylcarboxamide hydrochloride
NMR (400 MHz, DMSO-d 6 , δ): 1.11 (1H, s), 1.12-2.0 (12H, m), 2.98-3.06 (2H, m), 3.15-3.42 (6H, m), 3.51-3.57 (2H, m), 4.55 (1H, s), 4.75-4.82 (1H, m), 4.91-4.94 (1H, m), 6.21 (1H, d, J = 1.7Hz), 7.3-7.42 (10H, m ), 7.73 (2H, d, J = 4.1Hz)
(-) ESI-MS (m / z): 607 (MH) -

（４） Ｎ−［（３−アミノ−３−オキソプロピル）スルホニル］−３−（シクロヘキシルオキシ）−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エチル］−４−ビフェニルカルボキサミド塩酸塩
NMR (400 MHz, DMSO-d6, δ): 1.38-1.72 (10H, m), 2.3-2.7 (2H, m), 2.6-2.9 (2H, m), 2.9-3.2 (2H, m), 3.3-3.5 (4H, m), 4.8-4.9 (1H, m), 4.92-4.96 (1H, m), 6.22 (1H, d, J=3.4Hz), 7.03 (1H, s), 7.31-7.41 (8H, m), 7.52 (1H, s), 7.73 (2H, d, J=11.3Hz)
(+)ESI-MS (m/z): 594 (M+H)+ (遊離化合物) (4) N-[(3-amino-3-oxopropyl) sulfonyl] -3- (cyclohexyloxy) -4 '-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethyl ] -4-biphenylcarboxamide hydrochloride
NMR (400 MHz, DMSO-d 6 , δ): 1.38-1.72 (10H, m), 2.3-2.7 (2H, m), 2.6-2.9 (2H, m), 2.9-3.2 (2H, m), 3.3 -3.5 (4H, m), 4.8-4.9 (1H, m), 4.92-4.96 (1H, m), 6.22 (1H, d, J = 3.4Hz), 7.03 (1H, s), 7.31-7.41 (8H , m), 7.52 (1H, s), 7.73 (2H, d, J = 11.3Hz)
(+) ESI-MS (m / z): 594 (M + H) + (free compound)

（５） ３−（シクロヘキシルオキシ）−Ｎ−［（４−ヒドロキシブチル）スルホニル］−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エチル］−４−ビフェニルカルボキサミド塩酸塩
NMR (400 MHz, DMSO-d6, δ): 1.32-2.00 (14H, m), 3.06-3.65 (10H, m), 4.02 (1H, t, J=6.1Hz), 4.78-4.82 (1H, m), 4.99 (1H, d, J=9.4Hz), 6.2-6.23 (1H, m), 7.3-7.41 (10H, m), 7.7-7.74 (2H, m), 8.88 (1H, br s), 9.21 (1H, br s)
(-)ESI-MS (m/z): 593 (M-H)- (5) 3- (Cyclohexyloxy) -N-[(4-hydroxybutyl) sulfonyl] -4 ′-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethyl] -4- Biphenyl carboxamide hydrochloride
NMR (400 MHz, DMSO-d 6 , δ): 1.32-2.00 (14H, m), 3.06-3.65 (10H, m), 4.02 (1H, t, J = 6.1Hz), 4.78-4.82 (1H, m ), 4.99 (1H, d, J = 9.4Hz), 6.2-6.23 (1H, m), 7.3-7.41 (10H, m), 7.7-7.74 (2H, m), 8.88 (1H, br s), 9.21 (1H, br s)
(-) ESI-MS (m / z): 593 (MH) -

実施例２２
下記の化合物を実施例２と同様の方法にしたがい、次いで実施例３と同様の方法にしたがって得た。 Example 22
The following compound was obtained in the same manner as in Example 2, and then obtained according to the same method as in Example 3.

４−［（７Ｓ）−７−［［（２Ｒ）−２−（４−クロロフェニル）−２−ヒドロキシエチル］アミノ］−５，６，７，８−テトラヒドロ−２−ナフタレニル］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］ベンズアミド塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.4-2.4 (8H, m), 2.7-3.8 (6H, m), 4.11 (1H, m), 5.06 (1H, m), 6.34 (1H, m), 7.25 (1H, d, J=8.0Hz), 7.3-7.5 (6H, m), 7.80 (2H, d, J=8.0Hz), 8.02 (2H, d, J=8.0Hz)
ESI-MS (m/z): 542 (M+H) 4-[(7S) -7-[[(2R) -2- (4-chlorophenyl) -2-hydroxyethyl] amino] -5,6,7,8-tetrahydro-2-naphthalenyl] -N-[( 3-hydroxypropyl) sulfonyl] benzamide hydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 1.4-2.4 (8H, m), 2.7-3.8 (6H, m), 4.11 (1H, m), 5.06 (1H, m), 6.34 (1H, m ), 7.25 (1H, d, J = 8.0Hz), 7.3-7.5 (6H, m), 7.80 (2H, d, J = 8.0Hz), 8.02 (2H, d, J = 8.0Hz)
ESI-MS (m / z): 542 (M + H)

実施例２３
４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］−３−（イソプロピルチオ）−４−ビフェニルカルボン酸（１５０ｍｇ）のテトラヒドロフラン（１．５ｍｌ）中の溶液に、Ｎ，Ｎ’−カルボニルジイミダゾール（６４ｍｇ）を加え、室温で３０分間攪拌した。混合物に酢酸３−（アミノスルホニル）プロピル（６７ｍｇ）と１，８−ジアザビシクロ［５．４．０］−７−ウンデセン（５５μｌ）を加え、室温で攪拌し、次いで５０℃で３時間攪拌した。反応混合物を０．１Ｎ塩酸と酢酸エチルに注ぎ、有機層を分離した。有機層を水と食塩水で洗浄し、硫酸マグネシウムで乾燥後、真空濃縮して、酢酸３−［［［［４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］−３−（イソプロピルチオ）−４−ビフェニリル］カルボニル］アミノ］スルホニル］プロピル（７２ｍｇ）を得た。生成物（７２ｍｇ）のメタノール（２．０ｍｌ）とテトラヒドロフラン（２．０ｍｌ）中の溶液に、水酸化ナトリウム水溶液（１Ｎ、５３２μｌ）を加え、室温で１０分間攪拌した。混合物に塩酸水溶液（１Ｎ、５３２μｌ）を加え、酢酸エチルで希釈した。溶液を水と酢酸エチルに注ぎ、有機層を分離した。有機層を水と食塩水で洗浄し、硫酸マグネシウムで乾燥後、真空濃縮した。残留物をシリカゲルカラムクロマトグラフィーで精製して、［（２Ｒ）−２−（３−クロロフェニル）２−ヒドロキシエチル］［２−［４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−３’−（イソプロピルチオ）−４−ビフェニリル］エチル］カルバミン酸第三級ブチル（４９ｍｇ）を得た。
(-)ESI-MS (m/z): 689, 691 (M-H)- Example 23
4 ′-[2-[(Tertiary butoxycarbonyl) [(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] -3- (isopropylthio) -4-biphenylcarboxylic acid ( To a solution of 150 mg) in tetrahydrofuran (1.5 ml), N, N′-carbonyldiimidazole (64 mg) was added and stirred at room temperature for 30 minutes. To the mixture were added 3- (aminosulfonyl) propyl acetate (67 mg) and 1,8-diazabicyclo [5.4.0] -7-undecene (55 μl), and the mixture was stirred at room temperature, and then stirred at 50 ° C. for 3 hours. The reaction mixture was poured into 0.1N hydrochloric acid and ethyl acetate, and the organic layer was separated. The organic layer was washed with water and brine, dried over magnesium sulfate, concentrated in vacuo and acetic acid 3-[[[[4 '-[2-[(tertiary butoxycarbonyl) [(2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] amino] ethyl] -3- (isopropylthio) -4-biphenylyl] carbonyl] amino] sulfonyl] propyl (72 mg) was obtained. To a solution of the product (72 mg) in methanol (2.0 ml) and tetrahydrofuran (2.0 ml) was added aqueous sodium hydroxide solution (1N, 532 μl) and stirred at room temperature for 10 minutes. To the mixture was added aqueous hydrochloric acid (1N, 532 μl) and diluted with ethyl acetate. The solution was poured into water and ethyl acetate and the organic layer was separated. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography to obtain [(2R) -2- (3-chlorophenyl) 2-hydroxyethyl] [2- [4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl. ] -3 '-(Isopropylthio) -4-biphenylyl] ethyl] tertiary butyl carbamate (49 mg) was obtained.
(-) ESI-MS (m / z): 689, 691 (MH) -

実施例２４
下記の化合物を実施例２３と同様の方法にしたがって得た。 Example 24
The following compound was obtained according to the same method as in Example 23.

［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］［２−［３’−（イソプロピルチオ）−４’−［［［（２−メトキシエチル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］エチル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 655 (M-H)- [(2R) -2-hydroxy-2-phenylethyl] [2- [3 ′-(isopropylthio) -4 ′-[[[(2-methoxyethyl) sulfonyl] amino] carbonyl] -4-biphenylyl] ethyl ] Tertiary butyl carbamate
(-) ESI-MS (m / z): 655 (MH) -

実施例２５
［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］［２−［３’−（イソプロピルチオ）−４’−［［［（２−メトキシエチル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］エチル］カルバミン酸第三級ブチル（３．９２ｇ）の酢酸エチル（２０ｍｌ）中の溶液に、塩化水素／酢酸エチル溶液（４Ｍ、２０ｍｌ）を加え、室温で一夜攪拌した。生じた固形物を濾取し、乾燥して、４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エチル］−３−（イソプロピルチオ）−Ｎ−［（２−メトキシエチル）スルホニル］−４−ビフェニルカルボキサミド塩酸塩（３．１５ｇ）を得た。
NMR (200 MHz, DMSO-d6, δ): 1.26 (6H, d, J=6.6Hz), 3.06-3.28 (6H, m), 3.28 (3H, s), 3.61-3.78 (1H, m), 3.78 (4H, s), 4.97-5.03 (1H,m), 6.23 (1H, d, J=3.6Hz), 7.31-7.42 (7H, m), 7.55-7.64 (2H, m), 7.70-7.74 (3H, m), 8.91 (1H, br s), 9.25 (1H, br s), 12.2 (1H, br s)
(-)ESI-MS (m/z): 555 (M-H)- Example 25
[(2R) -2-hydroxy-2-phenylethyl] [2- [3 ′-(isopropylthio) -4 ′-[[[(2-methoxyethyl) sulfonyl] amino] carbonyl] -4-biphenylyl] ethyl To a solution of tertiary butyl carbamate (3.92 g) in ethyl acetate (20 ml) was added hydrogen chloride / ethyl acetate solution (4M, 20 ml) and stirred at room temperature overnight. The resulting solid was collected by filtration, dried and 4 ′-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethyl] -3- (isopropylthio) -N-[( 2-Methoxyethyl) sulfonyl] -4-biphenylcarboxamide hydrochloride (3.15 g) was obtained.
NMR (200 MHz, DMSO-d 6 , δ): 1.26 (6H, d, J = 6.6Hz), 3.06-3.28 (6H, m), 3.28 (3H, s), 3.61-3.78 (1H, m), 3.78 (4H, s), 4.97-5.03 (1H, m), 6.23 (1H, d, J = 3.6Hz), 7.31-7.42 (7H, m), 7.55-7.64 (2H, m), 7.70-7.74 ( 3H, m), 8.91 (1H, br s), 9.25 (1H, br s), 12.2 (1H, br s)
(-) ESI-MS (m / z): 555 (MH) -

実施例２６
［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］［２−（４−ヨードフェノキシ）エチル］カルバミン酸第三級ブチル（２５０ｍｇ）と［３−（シクロヘキシルアミノ）−４−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］フェニル］ホウ素酸（２５８ｍｇ）のトルエン（３．０ｍｌ）とエタノール（７５０μｌ）中の溶液に、１，１’−ビス（ジフェニルホスフィノ）フェロセン（２９ｍｇ）、炭酸ナトリウム水溶液（２Ｍ、８３０μｌ）と［１，１’−ビス（ジフェニルホスフィノ）フェロセン］ジクロロパラジウム（３８ｍｇ）を窒素雰囲気下に室温で加え、７５℃で２時間攪拌した。反応混合物を０．５Ｎ塩酸（２０ｍｌ）と酢酸エチル（２０ｍｌ）に注ぎ、活性炭を加え、室温で３０分間攪拌した。混合物を濾過し、有機層を分離した。有機層を食塩水で洗浄し、硫酸マグネシウムで乾燥後、真空濃縮した。残留物をシリカゲルカラムクロマトグラフィーで精製して、［２−［［３’−（シクロヘキシルアミノ）−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］オキシ］エチル］［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］カルバミン酸第三級ブチル（１２７ｍｇ）を得た。
(-)ESI-MS (m/z): 694 (M-H)- Example 26
[(2R) -2-Hydroxy-2-phenylethyl] [2- (4-iodophenoxy) ethyl] tertiary butyl carbamate (250 mg) and [3- (cyclohexylamino) -4-[[[(3 -Hydroxypropyl) sulfonyl] amino] carbonyl] phenyl] boronic acid (258 mg) in a solution of toluene (3.0 ml) and ethanol (750 μl), 1,1′-bis (diphenylphosphino) ferrocene (29 mg), An aqueous sodium carbonate solution (2M, 830 μl) and [1,1′-bis (diphenylphosphino) ferrocene] dichloropalladium (38 mg) were added at room temperature under a nitrogen atmosphere, and the mixture was stirred at 75 ° C. for 2 hours. The reaction mixture was poured into 0.5N hydrochloric acid (20 ml) and ethyl acetate (20 ml), activated carbon was added, and the mixture was stirred at room temperature for 30 min. The mixture was filtered and the organic layer was separated. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography to obtain [2-[[3 ′-(cyclohexylamino) -4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -4-biphenylyl] oxy]. Ethyl] [(2R) -2-hydroxy-2-phenylethyl] tertiary butyl carbamate (127 mg) was obtained.
(-) ESI-MS (m / z): 694 (MH) -

実施例２７
下記の化合物を実施例２６と同様の方法にしたがって得た。
（１） 酢酸３−［［［［４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エトキシ］−３−（イソプロピルチオ）−４−ビフェニリル］カルボニル］アミノ］スルホニル］プロピル
(-)ESI-MS (m/z): 713 (M-H)- Example 27
The following compound was obtained in the same manner as in Example 26.
(1) Acetic acid 3-[[[[4 '-[2-[(tertiary butoxycarbonyl) [(2R) -2-hydroxy-2-phenylethyl] amino] ethoxy] -3- (isopropylthio)- 4-biphenylyl] carbonyl] amino] sulfonyl] propyl
(-) ESI-MS (m / z): 713 (MH) -

（２） ［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］［２−［［４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−３’−（イソプロピルチオ）−４−ビフェニリル］オキシ］エチル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 671 (M-H)- (2) [(2R) -2-hydroxy-2-phenylethyl] [2-[[4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -3 ′-(isopropylthio) -4 -Biphenylyl] oxy] ethyl] tertiary butyl carbamate
(-) ESI-MS (m / z): 671 (MH) -

（３） 酢酸３−［［［［４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニリル］カルボニル］アミノ］スルホニル］プロピル
(-)ESI-MS (m/z): 755 (M-H)- (3) Acetic acid 3-[[[[4 '-[2-[(tertiary butoxycarbonyl) [(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] -3- ( (Cyclohexyloxy) -4-biphenylyl] carbonyl] amino] sulfonyl] propyl
(-) ESI-MS (m / z): 755 (MH) -

（４） 酢酸３−［［［［４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（３−フルオロフェニル）−２−ヒドロキシエチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニリル］カルボニル］アミノ］スルホニル］プロピル
(+)ESI-MS (m/z): 763 (M+Na)+ (4) Acetic acid 3-[[[[4 '-[2-[(tertiary butoxycarbonyl) [(2R) -2- (3-fluorophenyl) -2-hydroxyethyl] amino] ethyl] -3- (Cyclohexyloxy) -4-biphenylyl] carbonyl] amino] sulfonyl] propyl
(+) ESI-MS (m / z): 763 (M + Na) +

実施例２８
酢酸３−［［［［４’−［２−［（第三級ブトキシカルボニル）−［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニリル］カルボニル］アミノ］スルホニル］プロピル（２６９ｍｇ）の塩化水素／メタノール溶液（１０％、２．７ｍｌ）中の混合物を室温で一夜攪拌した。反応混合物を真空濃縮し、残留物をエタノール水溶液（５０％）から再結晶して、４’−［２−［［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４−ビフェニルカルボキサミド塩酸塩（１６１ｍｇ）を得た。
NMR (200 MHz, DMSO-d6, δ): 1.23-2.03 (12H, m), 2.98-3.32 (6H, m), 3.36-3.61 (4H, m), 4.72-4.89 (1H, m), 5.04 (1H, d, J=8.0Hz), 6.41 (1H, br s), 7.33-7.48 (8H, m), 7.67-7.82 (3H, m), 8.96 (1H, br s), 9.28 (1H, br s), 11.17 (1H, s)
(-)ESI-MS (m/z): 613 (M-H)- Example 28
Acetic acid 3-[[[[4 '-[2-[(tertiarybutoxycarbonyl)-[(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] -3- (cyclohexyloxy A mixture of) -4-biphenylyl] carbonyl] amino] sulfonyl] propyl (269 mg) in hydrogen chloride / methanol solution (10%, 2.7 ml) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was recrystallized from aqueous ethanol (50%) to give 4 ′-[2-[[(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl. ] -3- (cyclohexyloxy) -N-[(3-hydroxypropyl) sulfonyl] -4-biphenylcarboxamide hydrochloride (161 mg) was obtained.
NMR (200 MHz, DMSO-d 6 , δ): 1.23-2.03 (12H, m), 2.98-3.32 (6H, m), 3.36-3.61 (4H, m), 4.72-4.89 (1H, m), 5.04 (1H, d, J = 8.0Hz), 6.41 (1H, br s), 7.33-7.48 (8H, m), 7.67-7.82 (3H, m), 8.96 (1H, br s), 9.28 (1H, br s), 11.17 (1H, s)
(-) ESI-MS (m / z): 613 (MH) -

実施例２９
下記の化合物を実施例２８と同様の方法にしたがって得た。 Example 29
The following compound was obtained in the same manner as in Example 28.

３−（シクロヘキシルオキシ）−４’−［２−［［（２Ｒ）−２−（３−フルオロフェニル）−２−ヒドロキシエチル］アミノ］エチル］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４−ビフェニルカルボキサミド塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.39-1.94 (12H,m), 3.00-3.27 (6H, m), 3.48-3.59 (4H, m), 4.65-4.88 (2H, m), 5.03 (1H, d, J=9.5Hz), 6.36 (1H, d, J=3.5Hz), 7.11-7.51 (8H, m), 7.68-7.79 (3H, m), 9.44 (2H, br s)
(-)ESI-MS (m/z): 597 (M-H)- 3- (Cyclohexyloxy) -4 ′-[2-[[(2R) -2- (3-fluorophenyl) -2-hydroxyethyl] amino] ethyl] -N-[(3-hydroxypropyl) sulfonyl]- 4-biphenylcarboxamide hydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 1.39-1.94 (12H, m), 3.00-3.27 (6H, m), 3.48-3.59 (4H, m), 4.65-4.88 (2H, m), 5.03 (1H, d, J = 9.5Hz), 6.36 (1H, d, J = 3.5Hz), 7.11-7.51 (8H, m), 7.68-7.79 (3H, m), 9.44 (2H, br s)
(-) ESI-MS (m / z): 597 (MH) -

実施例３０
酢酸３−［［［［４’−［３−［（第三級ブトキシカルボニル）［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］プロピル］−３−イソブトキシ−４−ビフェニリル］カルボニル］アミノ］スルホニル］プロピル（１０８ｍｇ）のメタノール（１．０８ｍｌ）とテトラヒドロフラン（０．３２４ｍｌ）中の溶液に、１Ｎ水酸化ナトリウム水溶液（０．４５５ｍｌ）を加え、混合物を室温で４５分間攪拌した。反応混合物を減圧濃縮し、０．１Ｎ塩酸でｐＨ値を６．０に調整した。混合物を酢酸エチルで抽出（２回）し、抽出物を水と食塩水で洗浄し、硫酸マグネシウムで乾燥した。濾過後、溶媒を減圧留去して、［３−［４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−３’−イソブトキシ−４−ビフェニリル］プロピル］［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］カルバミン酸第三級ブチル（９１．１ｍｇ）を白色固形物（泡状物）として得た。
(-)ESI-MS (m/z): 668 (M-H)- Example 30
Acetic acid 3-[[[[4 '-[3-[(tertiarybutoxycarbonyl) [(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] propyl] -3-isobutoxy-4- To a solution of biphenylyl] carbonyl] amino] sulfonyl] propyl (108 mg) in methanol (1.08 ml) and tetrahydrofuran (0.324 ml) was added 1N aqueous sodium hydroxide solution (0.455 ml) and the mixture was stirred at room temperature for 45 minutes. Stir. The reaction mixture was concentrated under reduced pressure, and the pH value was adjusted to 6.0 with 0.1N hydrochloric acid. The mixture was extracted with ethyl acetate (twice) and the extract was washed with water and brine and dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and [3- [4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -3′-isobutoxy-4-biphenylyl] propyl] [(2R) — Tertiary butyl 2-hydroxy-2- (3-pyridyl) ethyl] carbamate (91.1 mg) was obtained as a white solid (foam).
(-) ESI-MS (m / z): 668 (MH) -

実施例３１
酢酸３−［［［［４’−［３−［（第三級ブトキシカルボニル）［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］プロピル］−３−イソプロポキシ−４−ビフェニリル］カルボニル］アミノ］スルホニル］プロピル（２２１ｍｇ）のメタノール（２．２１ｍｌ）とテトラヒドロフラン（１．１１ｍｌ）中の溶液に、１Ｎ水酸化ナトリウム（０．９５０ｍｌ）を加え、混合物を室温で１時間攪拌した。メタノールとテトラヒドロフランを減圧留去し、残留物に水（５０ｍｌ）を加えた。混合物を１Ｎ塩酸（ｐＨ＝５．４）で酸性にし、酢酸エチルで抽出（５０ｍｌ×２）した。合わせた有機層を水と食塩水で洗浄し、硫酸マグネシウムで乾燥した。濾過後、溶媒を減圧留去して、［３−［４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−３’−イソプロポキシ−４−ビフェニリル］プロピル］［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］カルバミン酸第三級ブチル（２１２ｍｇ）を白色固形物として得た。
(-)ESI-MS (m/z): 654 (M-H)- Example 31
Acetic acid 3-[[[[4 '-[3-[(tertiarybutoxycarbonyl) [(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] propyl] -3-isopropoxy-4 To a solution of -biphenylyl] carbonyl] amino] sulfonyl] propyl (221 mg) in methanol (2.21 ml) and tetrahydrofuran (1.11 ml) was added 1N sodium hydroxide (0.950 ml) and the mixture was at room temperature for 1 hour. Stir. Methanol and tetrahydrofuran were distilled off under reduced pressure, and water (50 ml) was added to the residue. The mixture was acidified with 1N hydrochloric acid (pH = 5.4) and extracted with ethyl acetate (50 ml × 2). The combined organic layers were washed with water and brine and dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain [3- [4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -3′-isopropoxy-4-biphenylyl] propyl] [(2R). Tertiary butyl-2-hydroxy-2- (3-pyridyl) ethyl] carbamate (212 mg) was obtained as a white solid.
(-) ESI-MS (m / z): 654 (MH) -

実施例３２
下記の化合物を製造例３と同様の方法にしたがって得た。 Example 32
The following compound was obtained according to the same method as in Production Example 3.

３−［［［［４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニリル］カルボニル］アミノ］スルホニル］プロパン酸
NMR (200 MHz, DMSO-d6, δ): 1.2-1.8 (10H, m), 1.33 (9H, s), 2.6-2.9 (4H, m), 3.0-3.6 (4H, m), 3.75 (2H, t, J=7Hz), 4.62-4.82 (2H, m), 5.45 (1H, br s), 7.2-7.4 (9H, m), 7.6-7.73 (3H, m)
(+)ESI-MS (m/z): 695 (M+H)+ 3-[[[[4 '-[2-[(Tertiary butoxycarbonyl) [(2R) -2-hydroxy-2-phenylethyl] amino] ethyl] -3- (cyclohexyloxy) -4-biphenylyl] Carbonyl] amino] sulfonyl] propanoic acid
NMR (200 MHz, DMSO-d 6 , δ): 1.2-1.8 (10H, m), 1.33 (9H, s), 2.6-2.9 (4H, m), 3.0-3.6 (4H, m), 3.75 (2H , t, J = 7Hz), 4.62-4.82 (2H, m), 5.45 (1H, br s), 7.2-7.4 (9H, m), 7.6-7.73 (3H, m)
(+) ESI-MS (m / z): 695 (M + H) +

実施例３３
窒素雰囲気下に塩化メチルマグネシウム（テトラヒドロフラン中３．０Ｍ、１１８μｌ）を、３−［［［［４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニリル］カルボニル］アミノ］スルホニル］プロパン酸メチル（５０．０ｍｇ）のテトラヒドロフラン（１．０ｍｌ）中の溶液に７８℃で加え、混合物を０℃で１０分間攪拌した。混合物を飽和塩化アンモニウム水溶液に注ぎ、生成物を酢酸エチルで抽出した。合わせた抽出物を食塩水で洗浄し、硫酸マグネシウムで乾燥後、溶媒を真空留去した。残留物をシリカゲルカラムクロマトグラフィーで精製して、［２−［３’−（シクロヘキシルオキシ）−４’−［［［（３−ヒドロキシ−３−メチルブチル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］エチル］［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］カルバミン酸第三級ブチル（３３．８ｍｇ）を得た。
(-)ESI-MS (m/z): 707 (M-H)- Example 33
Under a nitrogen atmosphere, methyl magnesium chloride (3.0 M in tetrahydrofuran, 118 μl) was added to 3-[[[[4 ′-[2-[(tertiary butoxycarbonyl) [(2R) -2-hydroxy-2-phenyl]. Ethyl] amino] ethyl] -3- (cyclohexyloxy) -4-biphenylyl] carbonyl] amino] sulfonyl] methyl propanoate (50.0 mg) in tetrahydrofuran (1.0 ml) was added at 78 ° C. and the mixture was added. Stir at 0 ° C. for 10 minutes. The mixture was poured into saturated aqueous ammonium chloride and the product was extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography to obtain [2- [3 ′-(cyclohexyloxy) -4 ′-[[[(3-hydroxy-3-methylbutyl) sulfonyl] amino] carbonyl] -4-biphenylyl]. Ethyl] [(2R) -2-hydroxy-2-phenylethyl] tertiary butyl carbamate (33.8 mg) was obtained.
(-) ESI-MS (m / z): 707 (MH) -

実施例３４
ナトリウムメトキシド（３８．１ｍｇ）を３−［［［［４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニリル］カルボニル］アミノ］スルホニル］プロパン酸メチル（１２５ｍｇ）のホルムアミド（２．０ｍｌ）中の溶液に室温で加えた。混合物を６０℃で１．５時間攪拌した。生成物を酢酸エチルで抽出した。合わせた抽出物を食塩水で洗浄し、硫酸マグネシウムで乾燥後、溶媒を真空留去した。残留物をシリカゲルカラムクロマトグラフィーで精製して、［２−［４’−［［［（３−アミノ−３−オキソプロピル）スルホニル］アミノ］カルボニル］−３’−（シクロヘキシルオキシ）−４−ビフェニリル］エチル］［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］カルバミン酸第三級ブチル（２２．０ｍｇ）を得た。
(+)ESI-MS (m/z): 694 (M+H)+ Example 34
Sodium methoxide (38.1 mg) was added to 3-[[[[4 ′-[2-[(tertiary butoxycarbonyl) [(2R) -2-hydroxy-2-phenylethyl] amino] ethyl] -3- To a solution of methyl (cyclohexyloxy) -4-biphenylyl] carbonyl] amino] sulfonyl] propanoate (125 mg) in formamide (2.0 ml) was added at room temperature. The mixture was stirred at 60 ° C. for 1.5 hours. The product was extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was purified by silica gel column chromatography to obtain [2- [4 ′-[[[(3-amino-3-oxopropyl) sulfonyl] amino] carbonyl] -3 ′-(cyclohexyloxy) -4-biphenylyl. ] Ethyl] [(2R) -2-hydroxy-2-phenylethyl] tertiary butyl carbamate (22.0 mg) was obtained.
(+) ESI-MS (m / z): 694 (M + H) +

実施例３５
１Ｎ水酸化ナトリウム（５７５μｌ）を酢酸４−［［［［４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニリル］カルボニル］アミノ］スルホニル］ブチル（２１２ｍｇ）のメタノール（４．２４ｍｌ）中の溶液に加えた。混合物を室温で一夜攪拌した。混合物から溶媒を真空留去した。残留物をシリカゲルカラムクロマトグラフィーで精製して、［２−［３’−（シクロヘキシルオキシ）−４’−［［［（４−ヒドロキシブチル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］エチル］［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］カルバミン酸第三級ブチル（１１１ｍｇ）を得た。
(-)ESI-MS (m/z): 695 (M+H)+ Example 35
1N sodium hydroxide (575 μl) was added to acetic acid 4-[[[[4 ′-[2-[(tertiary butoxycarbonyl) [(2R) -2-hydroxy-2-phenylethyl] amino] ethyl] -3- (Cyclohexyloxy) -4-biphenylyl] carbonyl] amino] sulfonyl] butyl (212 mg) was added to a solution in methanol (4.24 ml). The mixture was stirred overnight at room temperature. The solvent was removed from the mixture in vacuo. The residue was purified by silica gel column chromatography to obtain [2- [3 ′-(cyclohexyloxy) -4 ′-[[[(4-hydroxybutyl) sulfonyl] amino] carbonyl] -4-biphenylyl] ethyl] [ (2R) -2-hydroxy-2-phenylethyl] tertiary butyl carbamate (111 mg) was obtained.
(-) ESI-MS (m / z): 695 (M + H) +

製造例２７
３−ピリジンスルホン酸（１０．０ｇ）、五塩化リン（１３．１ｇ）と塩化ホスホリル（１０．０ｍｌ）の混合物を１３０℃で３．５時間攪拌した。溶液から溶媒を留去し、アセトンで希釈した。溶液から溶媒を留去し、水（２００ｍｌ）とイソプロピルエーテル（４００ｍｌ）に注いだ。有機層を分離し、食塩水で２回洗浄し、さらに飽和重炭酸ナトリウム水溶液と食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶液から溶媒を留去し、ヘキサン（２０ｍｌ）で覆い、塩化水素／酢酸エチル（４Ｎ、２０ｍｌ）を攪拌しながら滴下した。生じた固形物を濾取し、乾燥して、塩化３−ピリジンスルホニル塩酸塩（９．４９ｇ）を得た。
NMR (200 MHz, DMSO-d6, δ): 8.12 (1H, dd, J=5, 8Hz), 8.72 (1H, dd, J=1.8, 3Hz), 8.95 (1H, d, J=5.5Hz), 8.99 (1H, d, J=1Hz), 14.25 (1H, br s) Production Example 27
A mixture of 3-pyridinesulfonic acid (10.0 g), phosphorus pentachloride (13.1 g) and phosphoryl chloride (10.0 ml) was stirred at 130 ° C. for 3.5 hours. The solvent was removed from the solution and diluted with acetone. The solvent was distilled off from the solution and poured into water (200 ml) and isopropyl ether (400 ml). The organic layer was separated, washed twice with brine, further washed with saturated aqueous sodium bicarbonate and brine, and dried over magnesium sulfate. The solvent was distilled off from the solution, covered with hexane (20 ml), and hydrogen chloride / ethyl acetate (4N, 20 ml) was added dropwise with stirring. The resulting solid was collected by filtration and dried to give 3-pyridinesulfonyl chloride hydrochloride (9.49 g).
NMR (200 MHz, DMSO-d 6 , δ): 8.12 (1H, dd, J = 5, 8Hz), 8.72 (1H, dd, J = 1.8, 3Hz), 8.95 (1H, d, J = 5.5Hz) , 8.99 (1H, d, J = 1Hz), 14.25 (1H, br s)

製造例２８
塩化３−ピリジンスルホニル塩酸塩（５．００ｇ）のアセトン（８．５ｍｌ）中の懸濁液に、アンモニア水溶液（２８％、８．５ｍｌ）を０℃で滴下し、室温で３時間攪拌した。溶液から溶媒を留去して、水（約１０ｍｌ）、酢酸エチル（１００ｍｌ）とテトラヒドロフラン（１００ｍｌ）に注いだ。有機層を食塩水で２回洗浄し、水層を酢酸エチル（９０ｍｌ）とメタノール（１０ｍｌ）で抽出した。合わせた有機層を硫酸マグネシウムで乾燥後、溶媒を留去し、ヘキサンと酢酸エチル中で結晶化して、３−ピリジンスルホンアミド（３．４５ｇ）を得た。
(+)ESI-MS (m/z): 159 (M+H)+ Production Example 28
An aqueous ammonia solution (28%, 8.5 ml) was added dropwise at 0 ° C. to a suspension of 3-pyridinesulfonyl chloride hydrochloride (5.00 g) in acetone (8.5 ml), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off from the solution and poured into water (about 10 ml), ethyl acetate (100 ml) and tetrahydrofuran (100 ml). The organic layer was washed twice with brine and the aqueous layer was extracted with ethyl acetate (90 ml) and methanol (10 ml). The combined organic layer was dried over magnesium sulfate, the solvent was distilled off, and the residue was crystallized in hexane and ethyl acetate to obtain 3-pyridinesulfonamide (3.45 g).
(+) ESI-MS (m / z): 159 (M + H) +

製造例２９
亜硫酸ナトリウム（４１．７ｇ）の水（４０ｍｌ）中の懸濁液に、クロロアセトニトリル（２０．８ｍｌ）を加え、室温で４時間攪拌した。混合物から溶媒を留去し、メタノールで希釈した。混合物をメタノールとトルエンで希釈し、溶媒を留去し、エタノールから結晶化した。生じた固形物を６０℃で乾燥して、シアノメタンスルホン酸ナトリウム（５３．５ｇ）を得た。
(-)ESI-MS (m/z): 120 (M-Na)- Production Example 29
To a suspension of sodium sulfite (41.7 g) in water (40 ml), chloroacetonitrile (20.8 ml) was added and stirred at room temperature for 4 hours. The solvent was removed from the mixture and diluted with methanol. The mixture was diluted with methanol and toluene, the solvent was distilled off and crystallized from ethanol. The resulting solid was dried at 60 ° C. to obtain sodium cyanomethanesulfonate (53.5 g).
(-) ESI-MS (m / z): 120 (M-Na) -

製造例３０
シアノメタンスルホン酸ナトリウム（１５．０ｇ）、五塩化リン（２１．８ｇ）と塩化ホスホリル（２７．０ｍｌ）の混合物を窒素雰囲気下に７０℃で３時間攪拌した。固形物を濾去し、溶液から溶媒を留去して、塩化シアノメタンスルホニル（８．６６ｇ）を粗製油状物として得た。この化合物を、さらに精製することなく次の反応に用いた。 Production Example 30
A mixture of sodium cyanomethanesulfonate (15.0 g), phosphorus pentachloride (21.8 g) and phosphoryl chloride (27.0 ml) was stirred at 70 ° C. for 3 hours under a nitrogen atmosphere. The solid was filtered off and the solvent was removed from the solution to give cyanomethanesulfonyl chloride (8.66 g) as a crude oil. This compound was used in the next reaction without further purification.

製造例３１
粗製塩化シアノメタンスルホニル（８．６６ｇ）のジクロロメタン（５２．０ｍｌ）とテトラヒドロフラン（１３．０ｍｌ）中の溶液に、攪拌しながら１０℃以下で１時間アンモニアガスを吹き込んだ。褐色固形物を濾取し、メタノールで溶離した。溶液から溶媒を留去し、残留物をシリカゲルカラムクロマトグラフィーで精製して、１−シアノメタンスルホンアミド（１．３６ｇ）を得た。
(-)ESI-MS (m/z): 119 (M-H)- Production Example 31
A solution of crude cyanomethanesulfonyl chloride (8.66 g) in dichloromethane (52.0 ml) and tetrahydrofuran (13.0 ml) was bubbled with ammonia gas at 10 ° C. or lower for 1 hour with stirring. A brown solid was filtered off and eluted with methanol. The solvent was distilled off from the solution, and the residue was purified by silica gel column chromatography to obtain 1-cyanomethanesulfonamide (1.36 g).
(-) ESI-MS (m / z): 119 (MH) -

製造例３２
４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−フェニル−２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エチル］アミノ］エチル］−３−（イソプロピルチオ）−４−ビフェニルカルボン酸（５００ｍｇ）のＮ，Ｎ−ジメチルホルムアミド（５ｍｌ）中の溶液に、Ｎ，Ｎ’−カルボニルジイミダゾール（１５７ｍｇ）を加え、室温で３０分間攪拌した。混合物に３−ピリジンスルホンアミド（１５３ｍｇ）と１，８−ジアザビシクロ［５．４．０］−７−ウンデセン（１４５μｌ）を加え、室温で３時間攪拌した。反応混合物を０．１Ｎ塩酸と酢酸エチルに注ぎ、有機層を分離した。有機層を水と食塩水で洗浄し、硫酸マグネシウムで乾燥後、真空濃縮した。残留物をシリカゲルカラムクロマトグラフィーで精製して、［２−［３’−（イソプロピルチオ）−４’−［［（３−ピリジルスルホニル）アミノ］カルボニル］−４−ビフェニリル］エチル］［（２Ｒ）−２−フェニル−２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エチル］カルバミン酸第三級ブチル（６１３ｍｇ）を得た。
(-)ESI-MS (m/z): 758 (M-H)- Production Example 32
4 ′-[2-[(Tertiary butoxycarbonyl) [(2R) -2-phenyl-2- (tetrahydro-2H-pyran-2-yloxy) ethyl] amino] ethyl] -3- (isopropylthio)- To a solution of 4-biphenylcarboxylic acid (500 mg) in N, N-dimethylformamide (5 ml) was added N, N′-carbonyldiimidazole (157 mg) and stirred at room temperature for 30 minutes. To the mixture were added 3-pyridinesulfonamide (153 mg) and 1,8-diazabicyclo [5.4.0] -7-undecene (145 μl), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into 0.1N hydrochloric acid and ethyl acetate, and the organic layer was separated. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel column chromatography to obtain [2- [3 ′-(isopropylthio) -4 ′-[[(3-pyridylsulfonyl) amino] carbonyl] -4-biphenylyl] ethyl] [(2R) 2-Phenyl-2- (tetrahydro-2H-pyran-2-yloxy) ethyl] tertiary butyl carbamate (613 mg) was obtained.
(-) ESI-MS (m / z): 758 (MH) -

製造例３３〜製造例３５の下記化合物を製造例３２と同様の方法にしたがって得た。
製造例３３
［２−［４’−［［［（シアノメチル）スルホニル］アミノ］カルボニル］−３’−（イソプロピルチオ）−４−ビフェニリル］エチル］［（２Ｒ）−２−フェニル−２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エチル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 720 (M-H)- The following compounds of Production Example 33 to Production Example 35 were obtained in the same manner as in Production Example 32.
Production Example 33
[2- [4 ′-[[[(Cyanomethyl) sulfonyl] amino] carbonyl] -3 ′-(isopropylthio) -4-biphenylyl] ethyl] [(2R) -2-phenyl-2- (tetrahydro-2H- Pyran-2-yloxy) ethyl] tertiary butyl carbamate
(-) ESI-MS (m / z): 720 (MH) -

製造例３４
［（２Ｒ）−２−［［第三級ブチル（ジメチル）シリル］オキシ］−２−（３−ピリジル）エチル］［２−［３’−（シクロヘキシルオキシ）−４’−［［（３−ピリジルスルホニル）アミノ］カルボニル］−４−ビフェニリル］エチル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 813 (M-H)- Production Example 34
[(2R) -2-[[Tertiary butyl (dimethyl) silyl] oxy] -2- (3-pyridyl) ethyl] [2- [3 ′-(cyclohexyloxy) -4 ′-[[(3- Pyridylsulfonyl) amino] carbonyl] -4-biphenylyl] ethyl] tertiary butyl carbamate
(-) ESI-MS (m / z): 813 (MH) -

製造例３５
［（２Ｒ）−２−［［第三級ブチル（ジメチル）シリル］オキシ］−２−（３−ピリジル）エチル］［２−［４’−［［［（シアノメチル）スルホニル］アミノ］カルボニル］−３’−（シクロヘキシルオキシ）−４−ビフェニリル］エチル］カルバミン酸第三級ブチル
(-)ESI-MS (m/z): 776 (M-H)- Production Example 35
[(2R) -2-[[tert-butyl (dimethyl) silyl] oxy] -2- (3-pyridyl) ethyl] [2- [4 ′-[[[(cyanomethyl) sulfonyl] amino] carbonyl]- 3 ′-(Cyclohexyloxy) -4-biphenylyl] ethyl] tertiary butyl carbamate
(-) ESI-MS (m / z): 776 (MH) -

製造例３６
［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］［２−［（４−ヨードフェニル）アミノ］エチル］カルバミン酸第三級ブチル（２００ｍｇ）、［３−（シクロヘキシルオキシ）−４−（メトキシカルボニル）フェニル］ホウ素酸（１９３ｍｇ）とリン酸カリウム（２４６ｍｇ）のエタノール（１．５ｍｌ）中の溶液に、酢酸ビス（ジシクロヘキシルアミン）パラジウム（ＩＩ）（３２．９ｍｇ）を加え、混合物を窒素雰囲気下に６０℃で３時間攪拌した。８０℃に加温後、混合物を同温で３時間攪拌した。反応混合物に［３−（シクロヘキシルオキシ）−４−（メトキシカルボニル）フェニル］ホウ素酸（１０７ｍｇ）と酢酸ビス（ジシクロヘキシルアミン）パラジウム（ＩＩ）（１０．９ｍｇ）を加え、混合物を８０℃で３時間攪拌した。室温まで冷却後、反応混合物を酢酸エチルで希釈し、セライトケーキで濾過した。濾液を水と食塩水で洗浄し、硫酸マグネシウムで乾燥した。濾過後、溶媒を減圧留去して、粗製生成物を得て、これをシリカゲルカラムクロマトグラフィー（溶離溶媒：ヘキサン／酢酸エチル＝１／６〜１／２）で精製して、４’−［［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］アミノ］−３−（シクロヘキシルオキシ）−４−ビフェニルカルボン酸メチル（１３０ｍｇ）を白色固形物として得た。
(+)ESI-MS (m/z): 623 (M+H)+, 646 (M+Na)+ Production Example 36
[(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] [2-[(4-iodophenyl) amino] ethyl] tertiary butyl carbamate (200 mg), [3- (cyclohexyloxy)- To a solution of 4- (methoxycarbonyl) phenyl] boronic acid (193 mg) and potassium phosphate (246 mg) in ethanol (1.5 ml) was added bis (dicyclohexylamine) palladium (II) acetate (32.9 mg), The mixture was stirred at 60 ° C. for 3 hours under a nitrogen atmosphere. After warming to 80 ° C., the mixture was stirred at the same temperature for 3 hours. [3- (Cyclohexyloxy) -4- (methoxycarbonyl) phenyl] boronic acid (107 mg) and bis (dicyclohexylamine) palladium (II) acetate (10.9 mg) were added to the reaction mixture, and the mixture was stirred at 80 ° C. for 3 hours. Stir. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered through a celite cake. The filtrate was washed with water and brine and dried over magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/6 to 1/2), and 4 ′-[ [2-[(tertiary butoxycarbonyl) [(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] -3- (cyclohexyloxy) -4-biphenylcarboxylate ( 130 mg) was obtained as a white solid.
(+) ESI-MS (m / z): 623 (M + H) + , 646 (M + Na) +

製造例３７
４’−［［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］アミノ］−３−（シクロヘキシルオキシ）−４−ビフェニルカルボン酸メチル（１２５ｍｇ）のメタノール（１．７５０ｍｌ）とテトラヒドロフラン（０．９００ｍｌ）中の溶液に、１Ｎ水酸化ナトリウム水溶液（１．０５ｍｌ）を加え、混合物を室温で１日間攪拌した。反応混合物に１Ｎ水酸化ナトリウム水溶液（０．９００ｍｌ）を加え、混合物を室温で３日間攪拌した。反応混合物を減圧濃縮し、残留物に酢酸エチル（４０ｍｌ）と水（２０ｍｌ）を加えた。０．１Ｎ塩酸を加えてｐＨ値を５．７０に調整し、分離した有機層を水と食塩水で洗浄し、硫酸マグネシウムで乾燥した。濾過後、溶媒を留去して、４’−［［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］アミノ］−３−（シクロヘキシルオキシ）−４−ビフェニルカルボン酸（１２３ｍｇ）を黄色泡状物として得た。
(-)ESI-MS (m/z): 607 (M-H)- Production Example 37
4 ′-[[2-[(Tertiary butoxycarbonyl) [(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] -3- (cyclohexyloxy) -4-biphenyl To a solution of methyl carboxylate (125 mg) in methanol (1.750 ml) and tetrahydrofuran (0.900 ml) was added 1N aqueous sodium hydroxide (1.05 ml) and the mixture was stirred at room temperature for 1 day. To the reaction mixture was added 1N aqueous sodium hydroxide solution (0.900 ml), and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (40 ml) and water (20 ml) were added to the residue. 0.1N hydrochloric acid was added to adjust the pH value to 5.70, and the separated organic layer was washed with water and brine and dried over magnesium sulfate. After filtration, the solvent was distilled off and 4 ′-[[2-[(tertiarybutoxycarbonyl) [(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino]- 3- (Cyclohexyloxy) -4-biphenylcarboxylic acid (123 mg) was obtained as a yellow foam.
(-) ESI-MS (m / z): 607 (MH) -

製造例３８
４’−［［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］アミノ］−３−（シクロヘキシルオキシ）−４−ビフェニルカルボン酸メチル（１２５ｍｇ）のメタノール（１．７５０ｍｌ）とテトラヒドロフラン（０．９００ｍｌ）中の溶液に、１Ｎ水酸化ナトリウム水溶液（１．０５ｍｌ）を加え、混合物を室温で１日間攪拌した。反応混合物に１Ｎ水酸化ナトリウム水溶液（０．９００ｍｌ）を加え、混合物を室温で３日間攪拌した。反応混合物を減圧濃縮し、残留物に酢酸エチル（４０ｍｌ）と水（２０ｍｌ）を加えた。０．１Ｎ塩酸を加えてｐＨ値を５．７０に調整し、分離した有機層を水と食塩水で洗浄し、硫酸マグネシウムで乾燥した。濾過後、溶媒を留去して、４’−［［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］アミノ］−３−（シクロヘキシルオキシ）−４−ビフェニルカルボン酸（１２３ｍｇ）を黄色泡状物として得た。
(+)ESI-MS (m/z): 597 (M+H)+, 620 (M+Na)+ Production Example 38
4 ′-[[2-[(Tertiary butoxycarbonyl) [(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] -3- (cyclohexyloxy) -4-biphenyl To a solution of methyl carboxylate (125 mg) in methanol (1.750 ml) and tetrahydrofuran (0.900 ml) was added 1N aqueous sodium hydroxide (1.05 ml) and the mixture was stirred at room temperature for 1 day. To the reaction mixture was added 1N aqueous sodium hydroxide solution (0.900 ml), and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (40 ml) and water (20 ml) were added to the residue. 0.1N hydrochloric acid was added to adjust the pH value to 5.70, and the separated organic layer was washed with water and brine and dried over magnesium sulfate. After filtration, the solvent was distilled off and 4 ′-[[2-[(tertiarybutoxycarbonyl) [(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino]- 3- (Cyclohexyloxy) -4-biphenylcarboxylic acid (123 mg) was obtained as a yellow foam.
(+) ESI-MS (m / z): 597 (M + H) + , 620 (M + Na) +

製造例３９
下記の化合物を製造例３７と同様の方法にしたがって得た。 Production Example 39
The following compound was obtained according to the same method as in Production Example 37.

４’−［［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］アミノ］−３−イソブトキシ−４−ビフェニルカルボン酸
(-)ESI-MS (m/z): 582 (M-H)- 4 ′-[[2-[(Tertiary butoxycarbonyl) [(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] -3-isobutoxy-4-biphenylcarboxylic acid
(-) ESI-MS (m / z): 582 (MH) -

製造例４０
６−ブロモ−１−イソプロピル−１Ｈ−インドール−３−カルボン酸（１．９４ｇ）のＮ，Ｎ−ジメチルホルムアミド（９７ｍｌ）中の溶液に、炭酸カリウム（１．４３ｇ）とヨードメタン（０．５１４ｍｌ）を窒素雰囲気下に室温で加え、混合物を同温で３．５時間攪拌した。生じた混合物を水に注ぎ、水層を酢酸エチルで抽出した。有機層を水（３回）と食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１０／１〜５／１）で精製して、６−ブロモ−１−イソプロピル−１Ｈ−インドール−３−カルボン酸メチル（１．９ｇ）を得た。
(+)ESI-MS (m/z): 318, 320 (M+Na)+ Production Example 40
To a solution of 6-bromo-1-isopropyl-1H-indole-3-carboxylic acid (1.94 g) in N, N-dimethylformamide (97 ml) was added potassium carbonate (1.43 g) and iodomethane (0.514 ml). Was added at room temperature under a nitrogen atmosphere, and the mixture was stirred at the same temperature for 3.5 hours. The resulting mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with water (3 times) and brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10/1 to 5/1) to obtain methyl 6-bromo-1-isopropyl-1H-indole-3-carboxylate (1.9 g). It was.
(+) ESI-MS (m / z): 318, 320 (M + Na) +

製造例４１
６−ブロモ−２−ナフトエ酸メチル（５．０ｇ）の１，４−ジオキサン（５０ｍｌ）中の溶液に、４，４，４’，４’，５，５，５’，５’−オクタメチル−２，２’−ビ−１，３，２−ジオキサボロラン（５．３ｇ）、ジクロロビス（トリフェニルホスフィン）パラジウム（ＩＩ）（１．３ｇ）と酢酸カリウム（４．６ｇ）を窒素雰囲気下に室温で加え、混合物を９０℃で２時間攪拌した。生じた混合物を水に注ぎ、水層を酢酸エチルで抽出した。有機層を食塩水で洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。残留物をシリカゲルカラムクロマトグラフィー（溶離溶媒：クロロホルム）で精製して、６−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−２−ナフトエ酸メチル（３．６ｇ）を得た。
(+)ESI-MS (m/z): 313 (M+H)+ Production Example 41
To a solution of methyl 6-bromo-2-naphthoate (5.0 g) in 1,4-dioxane (50 ml) was added 4,4,4 ′, 4 ′, 5,5,5 ′, 5′-octamethyl- 2,2′-bi-1,3,2-dioxaborolane (5.3 g), dichlorobis (triphenylphosphine) palladium (II) (1.3 g) and potassium acetate (4.6 g) at room temperature under a nitrogen atmosphere. In addition, the mixture was stirred at 90 ° C. for 2 hours. The resulting mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform) to give methyl 6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2-naphthoate (3.6 g) was obtained.
(+) ESI-MS (m / z): 313 (M + H) +

製造例４２
下記の化合物を製造例４１と同様の方法にしたがって得た。 Production Example 42
The following compound was obtained according to the same method as in Production Example 41.

１−イソプロピル−６−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−１Ｈ−インドール−３−カルボン酸メチル
(+)ESI-MS (m/z): 366 (M+Na)+ 1-isopropyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indole-3-carboxylate methyl
(+) ESI-MS (m / z): 366 (M + Na) +

製造例４３
［２−（４−ブロモフェニル）エチル］［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］カルバミン酸第三級ブチル（５６０ｍｇ）と６−（４，４，５，５−テトラメチル−１，３，２−ジオキサボロラン−２−イル）−２−ナフトエ酸メチル（４６１ｍｇ）のＮ，Ｎ−ジメチルホルムアミド（５．６ｍｌ）中の溶液に、二塩化［１’，１’−ビス（ジフェニルホスフィノ）フェロセン］パラジウム（ＩＩ）／ジクロロメタン錯体（１５１ｍｇ）、１，１’−ビス（ジフェニルホスフィノ）フェロセン（１０２ｍｇ）と２Ｍ炭酸ナトリウム（２．０ｍｌ）を室温で加え、混合物を８０℃で４時間攪拌した。生じた混合物を水に注ぎ、水層を酢酸エチルで抽出した。有機層を水（３回）と食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝２／１）で精製して、６−［４−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］フェニル］−２−ナフトエ酸メチル（５１４ｍｇ）を得た。
(+)ESI-MS (m/z): 582, 584 (M+H)+ Production Example 43
[2- (4-Bromophenyl) ethyl] [(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] tertiary butyl carbamate (560 mg) and 6- (4,4,5,5- To a solution of methyl tetramethyl-1,3,2-dioxaborolan-2-yl) -2-naphthoate (461 mg) in N, N-dimethylformamide (5.6 ml) was added [1 ′, 1′- Bis (diphenylphosphino) ferrocene] palladium (II) / dichloromethane complex (151 mg), 1,1′-bis (diphenylphosphino) ferrocene (102 mg) and 2M sodium carbonate (2.0 ml) were added at room temperature and the mixture was Stir at 80 ° C. for 4 hours. The resulting mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with water (3 times) and brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give 6- [4- [2-[(tertiary butoxycarbonyl) [(2R) -2- (3-chlorophenyl)]. Methyl-2-hydroxyethyl] amino] ethyl] phenyl] -2-naphthoate (514 mg) was obtained.
(+) ESI-MS (m / z): 582, 584 (M + H) +

製造例４４
下記の化合物を製造例４３と同様の方法にしたがって得た。 Production Example 44
The following compound was obtained according to the same method as in Production Example 43.

６−［４−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］フェニル］−１−イソプロピル−１Ｈ−インドール−３−カルボン酸メチル
(+)ESI-MS (m/z): 613, 615 (M+Na)+ 6- [4- [2-[(Tertiary butoxycarbonyl) [(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] phenyl] -1-isopropyl-1H-indole-3 -Methyl carboxylate
(+) ESI-MS (m / z): 613, 615 (M + Na) +

製造例４５
６−［４−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］フェニル］−１−イソプロピル−１Ｈ−インドール−３−カルボン酸メチル（３４０ｍｇ）のジクロロメタン（５ｍｌ）中の溶液に、３，４−ジヒドロ−２Ｈ−ピラン（０．１０５ｍｌ）と触媒量のｐ−トルエンスルホン酸ピリジニウムを窒素雰囲気下に室温で加え、混合物を同温で１２時間攪拌した。生じた混合物を水に注ぎ、水層を酢酸エチルで抽出した。有機層を飽和重炭酸ナトリウム水溶液と食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝４／１）で精製して、６−［４−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（３−クロロフェニル）−２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エチル］アミノ］エチル］フェニル］−１−イソプロピル−１Ｈ−インドール−３−カルボン酸メチル（３１０ｍｇ）を得た。
(+)ESI-MS (m/z): 697 (M+Na)+ Production Example 45
6- [4- [2-[(Tertiary butoxycarbonyl) [(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] phenyl] -1-isopropyl-1H-indole-3 -To a solution of methyl carboxylate (340 mg) in dichloromethane (5 ml), 3,4-dihydro-2H-pyran (0.105 ml) and a catalytic amount of pyridinium p-toluenesulfonate at room temperature under nitrogen atmosphere, The mixture was stirred at the same temperature for 12 hours. The resulting mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to give 6- [4- [2-[(tertiary butoxycarbonyl) [(2R) -2- (3-chlorophenyl)]. Methyl-2- (tetrahydro-2H-pyran-2-yloxy) ethyl] amino] ethyl] phenyl] -1-isopropyl-1H-indole-3-carboxylate (310 mg) was obtained.
(+) ESI-MS (m / z): 697 (M + Na) +

製造例４６
６−［４−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］フェニル］−２−ナフトエ酸メチル（１０５ｍｇ）と１Ｎ水酸化ナトリウム（０．３７５ｍｌ）の１，４−ジオキサン（１ｍｌ）の混合物を室温で１２時間攪拌した。生じた混合物に１Ｎ塩酸（０．３７５ｍｌ）とクロロホルム−メタノール（５：１）を加えた。分離後、有機層を無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。残留物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝１０／１）で精製して、６−［４−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］フェニル］−２−ナフトエ酸（１００ｍｇ）を得た。
(-)ESI-MS (m/z): 544, 546 (M-H)- Production Example 46
With methyl 6- [4- [2-[(tertiary butoxycarbonyl) [(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] phenyl] -2-naphthoate (105 mg) A mixture of 1N sodium hydroxide (0.375 ml) of 1,4-dioxane (1 ml) was stirred at room temperature for 12 hours. To the resulting mixture was added 1N hydrochloric acid (0.375 ml) and chloroform-methanol (5: 1). After separation, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 10/1) to give 6- [4- [2-[(tertiary butoxycarbonyl) [(2R) -2- (3-chlorophenyl)- 2-Hydroxyethyl] amino] ethyl] phenyl] -2-naphthoic acid (100 mg) was obtained.
(-) ESI-MS (m / z): 544, 546 (MH) -

製造例４７
下記の化合物を製造例４６と同様の方法にしたがって得た。 Production Example 47
The following compound was obtained according to the same method as in Production Example 46.

６−［４−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（３−クロロフェニル）−２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エチル］アミノ］エチル］フェニル］−１−イソプロピル−１Ｈ−インドール−３−カルボン酸
(-)ESI-MS (m/z): 659, 661 (M-H)- 6- [4- [2-[(Tertiary butoxycarbonyl) [(2R) -2- (3-chlorophenyl) -2- (tetrahydro-2H-pyran-2-yloxy) ethyl] amino] ethyl] phenyl] -1-Isopropyl-1H-indole-3-carboxylic acid
(-) ESI-MS (m / z): 659, 661 (MH) -

製造例４８
６−［４−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（３−クロロフェニル）−２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エチル］アミノ］エチル］フェニル］−１−イソプロピル−１Ｈ−インドール−３−カルボン酸（１３１ｍｇ）のＮ，Ｎ−ジメチルホルムアミド（２ｍＬ）中の溶液に、１，１’−カルボニルジイミダゾール（３５ｍｇ）を窒素雰囲気下に室温で加え、混合物を同温で２．５時間攪拌した。これにメタンスルホンアミド（４６ｍｇ）と１，８−ジアザビシクロ［５．４．０］−７−ウンデセン（７２ｍｇ）を室温で加え、混合物を６０℃で１０時間攪拌した。生じた混合物を０．１Ｎ塩酸に注ぎ、水層を酢酸エチルで抽出した。有機層を０．１Ｎ塩酸（３回）と食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥後、溶媒を減圧留去した。残留物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝２００／１〜１００／１）で精製して、［（２Ｒ）−２−（３−クロロフェニル）−２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エチル］［２−［４−［１−イソプロピル−３−［［（メチルスルホニル）アミノ］カルボニル］−１Ｈ−インドール−６−イル］フェニル］エチル］カルバミン酸第三級ブチル（１３４ｍｇ）を得た。
(-)ESI-MS m/z: 736, 738 (M-H)- Production Example 48
6- [4- [2-[(Tertiary butoxycarbonyl) [(2R) -2- (3-chlorophenyl) -2- (tetrahydro-2H-pyran-2-yloxy) ethyl] amino] ethyl] phenyl] To a solution of -1-isopropyl-1H-indole-3-carboxylic acid (131 mg) in N, N-dimethylformamide (2 mL) was added 1,1′-carbonyldiimidazole (35 mg) at room temperature under a nitrogen atmosphere. The mixture was stirred at the same temperature for 2.5 hours. Methanesulfonamide (46 mg) and 1,8-diazabicyclo [5.4.0] -7-undecene (72 mg) were added thereto at room temperature, and the mixture was stirred at 60 ° C. for 10 hours. The resulting mixture was poured into 0.1N hydrochloric acid, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with 0.1N hydrochloric acid (3 times) and brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 200/1 to 100/1) to give [(2R) -2- (3-chlorophenyl) -2- (tetrahydro-2H-pyran-2-yloxy). ) Ethyl] [2- [4- [1-isopropyl-3-[[(methylsulfonyl) amino] carbonyl] -1H-indol-6-yl] phenyl] ethyl] tertiary butyl carbamate (134 mg). It was.
(-) ESI-MS m / z: 736, 738 (MH) -

製造例４９
下記の化合物を製造例４８と同様の方法にしたがって得た。 Production Example 49
The following compound was obtained according to the same method as in Production Example 48.

酢酸３−［［［［６−［４−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（３−クロロフェニル）−２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エチル］アミノ］エチル］フェニル］−１−イソプロピル−１Ｈ−インドール−３−イル］カルボニル］アミノ］スルホニル］プロピル
(+)ESI-MS (m/z): 846 (M+Na)+ 3-[[[[[6- [4- [2-[(tertiarybutoxycarbonyl) [(2R) -2- (3-chlorophenyl) -2- (tetrahydro-2H-pyran-2-yloxy) ethyl] ] Amino] ethyl] phenyl] -1-isopropyl-1H-indol-3-yl] carbonyl] amino] sulfonyl] propyl
(+) ESI-MS (m / z): 846 (M + Na) +

製造例５０
下記の化合物を製造例３８と同様の方法にしたがって得た。 Production Example 50
The following compound was obtained according to the same method as in Production Example 38.

４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニルカルボン酸メチル
NMR (200 MHz, DMSO-d6, δ): 1.17-1.98 (10H, m), 1.27 (9H, s), 2.65-2.81 (2H, m), 3.10-3.55 (4H, m), 3.79 (3H, s), 4.60-4.85 (2H, m), 5.61-5.68 (1H, m), 7.22-7.72 (9H, m), 8.44-8.49 (2H, m)
(+)ESI-MS (m/z): 575 (M+H)+ 4 ′-[2-[(Tertiary butoxycarbonyl) [(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] ethyl] -3- (cyclohexyloxy) -4-biphenylcarboxylate methyl ester
NMR (200 MHz, DMSO-d 6 , δ): 1.17-1.98 (10H, m), 1.27 (9H, s), 2.65-2.81 (2H, m), 3.10-3.55 (4H, m), 3.79 (3H , s), 4.60-4.85 (2H, m), 5.61-5.68 (1H, m), 7.22-7.72 (9H, m), 8.44-8.49 (2H, m)
(+) ESI-MS (m / z): 575 (M + H) +

製造例５１
４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニルカルボン酸メチルのＮ，Ｎ−ジメチルホルムアミド中の溶液に、イミダゾールと第三級ブチルジメチルクロロシランを室温で加えた。室温で１５分間、３５℃で３．５時間攪拌後、反応混合物を０．０５Ｎ塩酸に室温で注いだ。生成物を酢酸エチルで抽出した。合わせた抽出物を水と食塩水で洗浄し、硫酸マグネシウムで乾燥後、溶媒を留去した。残留物をシリカゲルカラムクロマトグラフィーで精製して、４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−［［第三級ブチル（ジメチル）シリル］オキシ］−２−（３−ピリジル）エチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニルカルボン酸メチル（１１．２２ｇ）を得た。
NMR (200 MHz, DMSO-d6, δ): -0.15 (3H, s), 0.00 (3H, s), 0.81 (9H, s), 1.31-1.38 (9H, s), 1.20-1.30 (10H, m), 2.73-2.80 (2H, m), 3.25-3.43 (4H, m), 3.38 (3H, s), 4.50-4.80 (1H, m), 4.85-5.11 (1H, m), 7.20-7.71 (9H, m), 8.47-8.52 (2H, m)
(+)ESI-MS (m/z): 689 (M+H)+ Production Example 51
4 ′-[2-[(Tertiary butoxycarbonyl) [(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] ethyl] -3- (cyclohexyloxy) -4-biphenylcarboxylate methyl ester To a solution of N, N-dimethylformamide was added imidazole and tertiary butyldimethylchlorosilane at room temperature. After stirring at room temperature for 15 minutes and at 35 ° C. for 3.5 hours, the reaction mixture was poured into 0.05N hydrochloric acid at room temperature. The product was extracted with ethyl acetate. The combined extracts were washed with water and brine, dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography, and 4 ′-[2-[(tertiary butoxycarbonyl) [(2R) -2-[[tertiary butyl (dimethyl) silyl] oxy] -2- ( Methyl 3-pyridyl) ethyl] amino] ethyl] -3- (cyclohexyloxy) -4-biphenylcarboxylate (11.22 g) was obtained.
NMR (200 MHz, DMSO-d 6 , δ): -0.15 (3H, s), 0.00 (3H, s), 0.81 (9H, s), 1.31-1.38 (9H, s), 1.20-1.30 (10H, m), 2.73-2.80 (2H, m), 3.25-3.43 (4H, m), 3.38 (3H, s), 4.50-4.80 (1H, m), 4.85-5.11 (1H, m), 7.20-7.71 ( 9H, m), 8.47-8.52 (2H, m)
(+) ESI-MS (m / z): 689 (M + H) +

製造例５２
下記の化合物を製造例３７と同様の方法にしたがって得た。 Production Example 52
The following compound was obtained according to the same method as in Production Example 37.

４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−［［第三級ブチル−（ジメチル）シリル］オキシ］−２−（３−ピリジル）エチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニルカルボン酸
NMR (200 MHz, DMSO-d6, δ): -0.14 (3H, s), 0.01 (3H, s), 0.82 (9H, s), 1.32-1.39 (9H, m), 1.21-1.99 (10H, m), 2.48-2.77 (2H, m), 3.25-3.43 (4H, m), 4.58-1.65 (1H, m), 4.90-5.20 (1H, m), 7.20-7.41 (5H, m), 7.58-7.78 (4H, m), 8.47-8.52 (2H, m)
(+)ESI-MS (m/z): 675 (M+H)+ 4 ′-[2-[(tertiarybutoxycarbonyl) [(2R) -2-[[tertiarybutyl- (dimethyl) silyl] oxy] -2- (3-pyridyl) ethyl] amino] ethyl]- 3- (Cyclohexyloxy) -4-biphenylcarboxylic acid
NMR (200 MHz, DMSO-d 6 , δ): -0.14 (3H, s), 0.01 (3H, s), 0.82 (9H, s), 1.32-1.39 (9H, m), 1.21-1.99 (10H, m), 2.48-2.77 (2H, m), 3.25-3.43 (4H, m), 4.58-1.65 (1H, m), 4.90-5.20 (1H, m), 7.20-7.41 (5H, m), 7.58- 7.78 (4H, m), 8.47-8.52 (2H, m)
(+) ESI-MS (m / z): 675 (M + H) +

製造例５３
下記の化合物を実施例４０と同様の方法にしたがって得た。 Production Example 53
The following compound was obtained according to the same method as in Example 40.

３−［［［［４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−［［第三級ブチル（ジメチル）シリル］オキシ］−２−（３−ピリジル）エチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニリル］カルボニル］アミノ］スルホニル］プロパン酸メチル
NMR (200 MHz, DMSO-d6, δ): -0.14 (3H, s), 0.00 (3H, s), 0.82 (9H, s), 1.28-1.32 (9H, m), 1.16-1.88 (10H, m), 1.90-2.00 (2H, m), 2.77-2.87 (3H, m), 2.55-3.50 (3H, m), 3.78 (2H, t, J=7.3Hz), 3.33 (3H, s), 4.74-4.80 (1H, m), 4.90-5.04 (1H, m), 7.26-7.42 (5H, m), 7.60-7.72 (4H, m), 8.49-7.82 (2H, m), 11.30 (1H, s)
(-)ESI-MS (m/z): 822 (M-H)- 3-[[[[4 '-[2-[(Tertiary butoxycarbonyl) [(2R) -2-[[Tertiary butyl (dimethyl) silyl] oxy] -2- (3-pyridyl) ethyl] Amino] ethyl] -3- (cyclohexyloxy) -4-biphenylyl] carbonyl] amino] sulfonyl] propanoic acid methyl ester
NMR (200 MHz, DMSO-d 6 , δ): -0.14 (3H, s), 0.00 (3H, s), 0.82 (9H, s), 1.28-1.32 (9H, m), 1.16-1.88 (10H, m), 1.90-2.00 (2H, m), 2.77-2.87 (3H, m), 2.55-3.50 (3H, m), 3.78 (2H, t, J = 7.3Hz), 3.33 (3H, s), 4.74 -4.80 (1H, m), 4.90-5.04 (1H, m), 7.26-7.42 (5H, m), 7.60-7.72 (4H, m), 8.49-7.82 (2H, m), 11.30 (1H, s)
(-) ESI-MS (m / z): 822 (MH) -

製造例５４
下記の化合物を製造例３７と同様の方法にしたがって得た。 Production Example 54
The following compound was obtained according to the same method as in Production Example 37.

３−［［［［４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−［［第三級ブチル（ジメチル）シリル］オキシ］−２−（３−ピリジル）エチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニリル］カルボニル］アミノ］スルホニル］プロピオン酸
NMR (200 MHz, DMSO-d6, δ): -0.13 (3H, s), 0.00 (3H, s), 0.82 (9H, s), 0.82-1.13 (9H, m), 1.13-1.80 (10H, m), 1.91-1.99 (2H, m), 2.70-2.78 (4H, m), 3.25-3.34 (2H, m), 3.74-3.78 (2H, m), 4.75-4.78 (1H, m), 4.90-5.02 (1H, m), 7.25-7.42 (5H, m), 7.64-7.76 (4H, m), 8.49-8.52 (2H, m)
(-)ESI-MS (m/z): 808 (M-H)- 3-[[[[4 '-[2-[(Tertiary butoxycarbonyl) [(2R) -2-[[Tertiary butyl (dimethyl) silyl] oxy] -2- (3-pyridyl) ethyl] Amino] ethyl] -3- (cyclohexyloxy) -4-biphenylyl] carbonyl] amino] sulfonyl] propionic acid
NMR (200 MHz, DMSO-d 6 , δ): -0.13 (3H, s), 0.00 (3H, s), 0.82 (9H, s), 0.82-1.13 (9H, m), 1.13-1.80 (10H, m), 1.91-1.99 (2H, m), 2.70-2.78 (4H, m), 3.25-3.34 (2H, m), 3.74-3.78 (2H, m), 4.75-4.78 (1H, m), 4.90- 5.02 (1H, m), 7.25-7.42 (5H, m), 7.64-7.76 (4H, m), 8.49-8.52 (2H, m)
(-) ESI-MS (m / z): 808 (MH) -

製造例５５
下記の化合物を実施例３３と同様の方法にしたがって得た。 Production Example 55
The following compound was obtained in the same manner as in Example 33.

［（２Ｒ）−２−［［第三級ブチル（ジメチル）シリル］オキシ］−２−（３−ピリジル）エチル］［２−［３’−（シクロヘキシルオキシ）−４’−［［［（３−ヒドロキシ−３−メチルブチル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］エチル］カルバミン酸第三級ブチル
NMR (200 MHz, DMSO-d6, δ): -0.14 (3H, s), 0.00 (3H, s), 0.82 (9H, s), 1.11 (6H, s), 1.71-1.21 (9H, m), 1.20-1.8 (10H, m), 1.95-2.05 (2H, m), 2.70-2.9 (2H, m), 3.23-3.60 (6H, m), 4.54 (1H, s), 4.76-4.82 (1H, m), 4.95-5.38 (1H, m), 7.26-7.42 (5H, m), 7.64-7.73 (4H, m), 8.49-8.52 (2H, m), 11.10 (1H, s)
(+)ESI-MS (m/z): 825 (M+H)+ [(2R) -2-[[Tertiary butyl (dimethyl) silyl] oxy] -2- (3-pyridyl) ethyl] [2- [3 ′-(cyclohexyloxy) -4 ′-[[[(3 -Hydroxy-3-methylbutyl) sulfonyl] amino] carbonyl] -4-biphenylyl] ethyl] tertiary butyl carbamate
NMR (200 MHz, DMSO-d 6 , δ): -0.14 (3H, s), 0.00 (3H, s), 0.82 (9H, s), 1.11 (6H, s), 1.71-1.21 (9H, m) , 1.20-1.8 (10H, m), 1.95-2.05 (2H, m), 2.70-2.9 (2H, m), 3.23-3.60 (6H, m), 4.54 (1H, s), 4.76-4.82 (1H, m), 4.95-5.38 (1H, m), 7.26-7.42 (5H, m), 7.64-7.73 (4H, m), 8.49-8.52 (2H, m), 11.10 (1H, s)
(+) ESI-MS (m / z): 825 (M + H) +

製造例５６
［（２Ｒ）−２−［［第三級ブチル（ジメチル）シリル］オキシ］−２−（３−ピリジル）エチル］［２−［４’−［［［（シアノメチル）スルホニル］アミノ］カルボニル］−３’−（シクロヘキシルオキシ）−４−ビフェニリル］エチル］カルバミン酸第三級ブチル（５２．９ｍｇ）のジメチルスルホキシド（１．０ｍｌ）中の溶液に、炭酸カリウム（２８．３ｍｇ）と３０％過酸化水素水溶液（１００μｌ）を０℃で加えた。室温で１６時間攪拌後、１Ｎ塩酸を反応混合物に加えた。生成物を酢酸エチルで抽出した。合わせた抽出物を食塩水で洗浄し、硫酸マグネシウムで乾燥後、溶媒を留去した。残留物を分取薄層クロマトグラフィー（クロロホルム／メタノール＝９５／５）で精製して、［２−［４’−［［［（２−アミノ−２−オキソエチル）スルホニル］アミノ］カルボニル］−３’−（シクロヘキシルオキシ）−４−ビフェニリル］エチル］［（２Ｒ）−２−［［第三級ブチル（ジメチル）シリル］オキシ］−２−（３−ピリジル）エチル］カルバミン酸第三級ブチル（３０．０ｍｇ）を得た。
(-)ESI-MS (m/z): 793 (M-H)- Production Example 56
[(2R) -2-[[tert-butyl (dimethyl) silyl] oxy] -2- (3-pyridyl) ethyl] [2- [4 ′-[[[(cyanomethyl) sulfonyl] amino] carbonyl]- 3 ′-(Cyclohexyloxy) -4-biphenylyl] ethyl] tertiary butyl carbamate (52.9 mg) in dimethyl sulfoxide (1.0 ml) was added to potassium carbonate (28.3 mg) and 30% peroxide. Aqueous hydrogen solution (100 μl) was added at 0 ° C. After stirring at room temperature for 16 hours, 1N hydrochloric acid was added to the reaction mixture. The product was extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by preparative thin layer chromatography (chloroform / methanol = 95/5) to give [2- [4 ′-[[[(2-amino-2-oxoethyl) sulfonyl] amino] carbonyl] -3. '-(Cyclohexyloxy) -4-biphenylyl] ethyl] [(2R) -2-[[tert-butyl (dimethyl) silyl] oxy] -2- (3-pyridyl) ethyl] tertiary butyl carbamate ( 30.0 mg) was obtained.
(-) ESI-MS (m / z): 793 (MH) -

製造例５７
下記の化合物を実施例４０と同様の方法にしたがって得た。 Production Example 57
The following compound was obtained according to the same method as in Example 40.

酢酸４−［［［［４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−［［第三級ブチル（ジメチル）シリル］オキシ］−２−（３−ピリジル）エチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニリル］カルボニル］アミノ］スルホニル］ブチル
NMR (200 MHz, DMSO-d6, δ): -0.15 (3H, s), 0.00 (3H, s), 0.82 (9H, s), 1.28-1.32 (9H, m), 1.26-2.00 (14H, m), 1.97 (3H, s), 2.75-2.79 (2H, m), 3.24-3.56 (6H, m), 3.98-4.04 (2H, m), 4.76-4.80 (1H, m), 4.94-5.04 (1H, m), 7.26-7.41 (5H, m), 7.63-7.72 (4H, m), 8.49-8.52 (2H, m), 11.18 (1H, s)
(-)ESI-MS (m/z): 850 (M-2H)- 4-[[[[[4 '-[2-[(Tertiary butoxycarbonyl)] [(2R) -2-[[Tertiary butyl (dimethyl) silyl] oxy] -2- (3-pyridyl) ethyl acetate Amino] ethyl] -3- (cyclohexyloxy) -4-biphenylyl] carbonyl] amino] sulfonyl] butyl
NMR (200 MHz, DMSO-d 6 , δ): -0.15 (3H, s), 0.00 (3H, s), 0.82 (9H, s), 1.28-1.32 (9H, m), 1.26-2.00 (14H, m), 1.97 (3H, s), 2.75-2.79 (2H, m), 3.24-3.56 (6H, m), 3.98-4.04 (2H, m), 4.76-4.80 (1H, m), 4.94-5.04 ( 1H, m), 7.26-7.41 (5H, m), 7.63-7.72 (4H, m), 8.49-8.52 (2H, m), 11.18 (1H, s)
(-) ESI-MS (m / z): 850 (M-2H) -

製造例５８
下記の化合物を実施例３５と同様の方法にしたがって得た。 Production Example 58
The following compound was obtained according to the same method as in Example 35.

［（２Ｒ）−２−［［第三級ブチル（ジメチル）シリル］オキシ］−２−（３−ピリジル）エチル］［２−［３’−（シクロヘキシルオキシ）−４’−［［［（４−ヒドロキシブチル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］エチル］カルバミン酸第三級ブチル
NMR (200 MHz, DMSO-d6, δ): -0.15 (3H, s), 0.00 (3H, s), 0.82 (9H, s), 1.23-1.28 (9H, m), 1.22-2.10 (14H, m), 2.73-2.80 (2H, m), 3.20-3.58 (8H, m), 4.49 (1H, t, J=5Hz), 4.76-4.80 (1H, m), 4.95-5.05 (1H, m), 7.25-7.41 (5H, m), 7.62-7.72 (4H, m), 8.49-8.52 (2H, m), 11.10 (H, s)
(-)ESI-MS (m/z): 809 (M-H)- [(2R) -2-[[Tertiary butyl (dimethyl) silyl] oxy] -2- (3-pyridyl) ethyl] [2- [3 '-(cyclohexyloxy) -4'-[[[(4 -Hydroxybutyl) sulfonyl] amino] carbonyl] -4-biphenylyl] ethyl] tertiary butyl carbamate
NMR (200 MHz, DMSO-d 6 , δ): -0.15 (3H, s), 0.00 (3H, s), 0.82 (9H, s), 1.23-1.28 (9H, m), 1.22-2.10 (14H, m), 2.73-2.80 (2H, m), 3.20-3.58 (8H, m), 4.49 (1H, t, J = 5Hz), 4.76-4.80 (1H, m), 4.95-5.05 (1H, m), 7.25-7.41 (5H, m), 7.62-7.72 (4H, m), 8.49-8.52 (2H, m), 11.10 (H, s)
(-) ESI-MS (m / z): 809 (MH) -

製造例５９
下記の化合物を製造例３８と同様の方法にしたがって得た。 Production Example 59
The following compound was obtained according to the same method as in Production Example 38.

４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニルカルボン酸メチル
NMR (200 MHz, DMSO-d6, δ): 1.43 (9H, s), 1.20-2.00 (10H, m), 2.64-2.98 (2H, m), 3.02-3.65 (4H, m), 3.83 (3H, s), 4.38-4.48 (1H, m), 4.84-4.91 (1H, m), 7.12-7.52 (10H, m), 7.84 (1H, d, J=8.5Hz)
(+)ESI-MS (m/z): 631 (M+Na)+ 4 ′-[2-[(Tertiary butoxycarbonyl) [(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] -3- (cyclohexyloxy) -4-biphenylcarboxylate methyl ester
NMR (200 MHz, DMSO-d 6 , δ): 1.43 (9H, s), 1.20-2.00 (10H, m), 2.64-2.98 (2H, m), 3.02-3.65 (4H, m), 3.83 (3H , s), 4.38-4.48 (1H, m), 4.84-4.91 (1H, m), 7.12-7.52 (10H, m), 7.84 (1H, d, J = 8.5Hz)
(+) ESI-MS (m / z): 631 (M + Na) +

製造例６０
下記の化合物を製造例５１と同様の方法にしたがって得た。 Production Example 60
The following compound was obtained according to the same method as in Production Example 51.

４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−［［第三級ブチル（ジメチル）シリル］オキシ］−２−（３−クロロフェニル）エチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニルカルボン酸メチル
NMR (200 MHz, DMSO-d6, δ): -0.11 (3H, s), 0.10 (3H, s), 0.87-0.90 (9H, m), 1.39-1.45 (9H, m), 1.35-2.00 (10H, m), 2.72-3.89 (6H, m), 3.89 (3H, s), 4.40-4.43 (1H, m), 5.03-5.07 (1H, m), 7.12-7.38 (8H, m), 7.46-7.50 (2H, m), 7.84 (1H, d, J=8.5Hz)
(+)ESI-MS (m/z): 744 (M+Na)+ 4 ′-[2-[(tertiarybutoxycarbonyl) [(2R) -2-[[tertiarybutyl (dimethyl) silyl] oxy] -2- (3-chlorophenyl) ethyl] amino] ethyl] -3 -(Cyclohexyloxy) -4-biphenylcarboxylate methyl ester
NMR (200 MHz, DMSO-d 6 , δ): -0.11 (3H, s), 0.10 (3H, s), 0.87-0.90 (9H, m), 1.39-1.45 (9H, m), 1.35-2.00 ( 10H, m), 2.72-3.89 (6H, m), 3.89 (3H, s), 4.40-4.43 (1H, m), 5.03-5.07 (1H, m), 7.12-7.38 (8H, m), 7.46- 7.50 (2H, m), 7.84 (1H, d, J = 8.5Hz)
(+) ESI-MS (m / z): 744 (M + Na) +

製造例６１
下記の化合物を製造例３７と同様の方法にしたがって得た。 Production Example 61
The following compound was obtained according to the same method as in Production Example 37.

４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−［［第三級ブチル（ジメチル）シリル］オキシ］−２−（３−クロロフェニル）エチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニルカルボン酸
NMR (200 MHz, DMSO-d6, δ): -0.13 (3H, s), 0.00 (3H, s), 0.83 (9H, s), 1.30-1.34 (9H, m), 1.21-1.99 (10H, m), 2.52-2.80 (2H, m), 3.20-3.49 (4H, m), 4.59-4.65 (1H, m), 4.87-4.99 (1H, m), 7.21-7.70 (11H, m)
(-)ESI-MS (m/z): 706 (M-H)- 4 ′-[2-[(tertiarybutoxycarbonyl) [(2R) -2-[[tertiarybutyl (dimethyl) silyl] oxy] -2- (3-chlorophenyl) ethyl] amino] ethyl] -3 -(Cyclohexyloxy) -4-biphenylcarboxylic acid
NMR (200 MHz, DMSO-d 6 , δ): -0.13 (3H, s), 0.00 (3H, s), 0.83 (9H, s), 1.30-1.34 (9H, m), 1.21-1.99 (10H, m), 2.52-2.80 (2H, m), 3.20-3.49 (4H, m), 4.59-4.65 (1H, m), 4.87-4.99 (1H, m), 7.21-7.70 (11H, m)
(-) ESI-MS (m / z): 706 (MH) -

製造例６２
下記の化合物を実施例４０と同様の方法にしたがって得た。 Production Example 62
The following compound was obtained according to the same method as in Example 40.

［（２Ｒ）−２−［［第三級ブチル（ジメチル）シリル］オキシ］−２−（３−クロロフェニル）エチル］［２−［４’−［［［（シアノメチル）スルホニル］アミノ］カルボニル］−３’−（シクロヘキシルオキシ）−４−ビフェニリル］エチル］カルバミン酸第三級ブチル
NMR (200 MHz, DMSO-d6, δ): -0.14 (3H, s), 0.00 (3H, s), 0.83 (9H, s), 1.29-1.34 (9H, m), 1.20-2.00 (10H, m), 2.72-2.81 (2H, m), 3.20-0.48 (4H, m), 4.70-4.76 (1H, m), 4.88-4.99 (1H, m), 5.24 (2H, s), 7.25-7.43 (8H, m), 7.63-7.68 (3H, m)
(-)ESI-MS (m/z): 808 (M-H)- [(2R) -2-[[Tertiary butyl (dimethyl) silyl] oxy] -2- (3-chlorophenyl) ethyl] [2- [4 ′-[[[(cyanomethyl) sulfonyl] amino] carbonyl]- 3 ′-(Cyclohexyloxy) -4-biphenylyl] ethyl] tertiary butyl carbamate
NMR (200 MHz, DMSO-d 6 , δ): -0.14 (3H, s), 0.00 (3H, s), 0.83 (9H, s), 1.29-1.34 (9H, m), 1.20-2.00 (10H, m), 2.72-2.81 (2H, m), 3.20-0.48 (4H, m), 4.70-4.76 (1H, m), 4.88-4.99 (1H, m), 5.24 (2H, s), 7.25-7.43 ( 8H, m), 7.63-7.68 (3H, m)
(-) ESI-MS (m / z): 808 (MH) -

製造例６３
下記の化合物を製造例５６と同様の方法にしたがって得た。 Production Example 63
The following compound was obtained according to the same method as in Production Example 56.

［２−［４’−［［［（２−アミノ−２−オキソエチル）スルホニル］アミノ］カルボニル］−３’−（シクロヘキシルオキシ）−４−ビフェニリル］エチル］−［（２Ｒ）−２−［［第三級ブチル（ジメチル）シリル］オキシ］−２−（３−クロロフェニル）エチル］カルバミン酸第三級ブチル
NMR (200 MHz, DMSO-d6, δ): -0.13 (3H, s), 0.00 (3H, s), 0.83 (9H, s), 1.29-1.33 (9H, m), 1.20-2.00 (10H, m), 2.52-2.81 (2H, m), 3.20-3.48 (4H, m), 4.35 (2H, s), 4.81-4.99 (2H, m), 7.25-7.84 (11H, m), 11.20 (1H, s)
(-)ESI-MS (m/z): 826 (M-H)- [2- [4 ′-[[[(2-Amino-2-oxoethyl) sulfonyl] amino] carbonyl] -3 ′-(cyclohexyloxy) -4-biphenylyl] ethyl]-[(2R) -2-[[ Tert-butyl (dimethyl) silyl] oxy] -2- (3-chlorophenyl) ethyl] tertiary butyl carbamate
NMR (200 MHz, DMSO-d 6 , δ): -0.13 (3H, s), 0.00 (3H, s), 0.83 (9H, s), 1.29-1.33 (9H, m), 1.20-2.00 (10H, m), 2.52-2.81 (2H, m), 3.20-3.48 (4H, m), 4.35 (2H, s), 4.81-4.99 (2H, m), 7.25-7.84 (11H, m), 11.20 (1H, s)
(-) ESI-MS (m / z): 826 (MH) -

製造例６４
［（２Ｒ）−２−（３−クロロフェニル）−２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エチル］［２−［４−［１−イソプロピル−３−［［（メチルスルホニル）アミノ］カルボニル］−１Ｈ−インドール−６−イル］フェニル］エチル］カルバミン酸第三級ブチル（１３２ｍｇ）、１０％塩化水素／メタノール（２ｍｌ）と４Ｎ塩化水素／１，４−ジオキサン（２ｍｌ）の混合物を室温で１２時間攪拌した。生じた混合物から溶媒を減圧留去した。残留物を逆相カラムクロマトグラフィーで精製し、１Ｎ塩酸で処理して、６−［４−［２−［［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］フェニル］−１−イソプロピル−Ｎ−（メチルスルホニル）−１Ｈ−インドール−３−カルボキサミド塩酸塩（８１ｍｇ）を得た。
NMR (200 MHz, DMSO-d6, δ): 1.52 (6H, d, J=6.5Hz), 3.00-3.45 (6H, m), 3.39 (3H, s), 4.90-5.10 (2H, m), 7.30-7.60 (7H, m), 7.76 (2H, d, J=8.2Hz), 7.91 (1H, s), 8.19 (1H, d, J=8.3Hz), 8.65 (1H, s)
(-)ESI-MS (m/z): 552 (M-HCl-H)- Production Example 64
[(2R) -2- (3-chlorophenyl) -2- (tetrahydro-2H-pyran-2-yloxy) ethyl] [2- [4- [1-isopropyl-3-[[(methylsulfonyl) amino] carbonyl ] -1H-indol-6-yl] phenyl] ethyl] tertiary butyl carbamate (132 mg), a mixture of 10% hydrogen chloride / methanol (2 ml) and 4N hydrogen chloride / 1,4-dioxane (2 ml) at room temperature. For 12 hours. The solvent was distilled off from the resulting mixture under reduced pressure. The residue was purified by reverse phase column chromatography and treated with 1N hydrochloric acid to give 6- [4- [2-[[(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl]. Phenyl] -1-isopropyl-N- (methylsulfonyl) -1H-indole-3-carboxamide hydrochloride (81 mg) was obtained.
NMR (200 MHz, DMSO-d 6 , δ): 1.52 (6H, d, J = 6.5Hz), 3.00-3.45 (6H, m), 3.39 (3H, s), 4.90-5.10 (2H, m), 7.30-7.60 (7H, m), 7.76 (2H, d, J = 8.2Hz), 7.91 (1H, s), 8.19 (1H, d, J = 8.3Hz), 8.65 (1H, s)
(-) ESI-MS (m / z): 552 (M-HCl-H) -

製造例６５
下記の化合物を製造例４３と同様の方法にしたがって得た。 Production Example 65
The following compound was obtained according to the same method as in Production Example 43.

４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−フェニル−２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エチル］アミノ］エチル］−３−（イソプロピルチオ）−４−ビフェニルカルボン酸メチル
(+)ESI-MS (m/z): 656 (M+Na)+ 4 ′-[2-[(Tertiary butoxycarbonyl) [(2R) -2-phenyl-2- (tetrahydro-2H-pyran-2-yloxy) ethyl] amino] ethyl] -3- (isopropylthio)- Methyl 4-biphenylcarboxylate
(+) ESI-MS (m / z): 656 (M + Na) +

製造例６６
下記の化合物を実施例２と同様の方法にしたがって得た。 Production Example 66
The following compound was obtained according to the same method as in Example 2.

４’−［２−［（第三級ブトキシカルボニル）アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニルカルボン酸メチル
(+)ESI-MS (m/z): 454 (M+H)+ 4 ′-[2-[(Tertiary butoxycarbonyl) amino] ethyl] -3- (cyclohexyloxy) -4-biphenylcarboxylate methyl ester
(+) ESI-MS (m / z): 454 (M + H) +

製造例６７
下記の化合物を製造例３と同様の方法にしたがって得た。 Production Example 67
The following compound was obtained according to the same method as in Production Example 3.

４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−フェニル−２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エチル］アミノ］エチル］−３−（イソプロピルチオ）−４−ビフェニルカルボン酸
(-)ESI-MS (m/z): 618 (M-H)- 4 ′-[2-[(Tertiary butoxycarbonyl) [(2R) -2-phenyl-2- (tetrahydro-2H-pyran-2-yloxy) ethyl] amino] ethyl] -3- (isopropylthio)- 4-biphenylcarboxylic acid
(-) ESI-MS (m / z): 618 (MH) -

製造例６８
４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（６−クロロ−３−ピリジル）−２−ヒドロキシエチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニルカルボン酸メチル（１．４３ｇ）のジクロロメタン（２５ｍｌ）中の溶液に、３，４−ジヒドロ−２Ｈ−ピラン（０．６４ｍｌ）とｐ−トルエンスルホン酸ピリジニウム（１１８ｍｇ）を室温で加え、混合物を窒素雰囲気下に２日間攪拌した。混合物を酢酸エチルで希釈し、水と食塩水で洗浄し、硫酸ナトリウムで乾燥後、溶媒を減圧留去して、残留物（２．３４ｇ）を得た。上記残留物のメタノール（８ｍｌ）／テトラヒドロフラン（８ｍｌ）中の溶液に、水酸化ナトリウム水溶液（１Ｎ、８ｍｌ）を室温で加え、混合物を室温で一夜攪拌した。混合溶液を塩酸水溶液（１Ｎ）で酸性にし、水に注ぎ、酢酸エチルで抽出した。有機層を食塩水で洗浄し、硫酸ナトリウムで乾燥後、溶媒を減圧留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝６／４）で精製して、４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（６−クロロ−３−ピリジル）−２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニルカルボン酸（１．４２ｇ）を得た。
(-)ESI-MS (m/z): 677 (M-H)- Production Example 68
4 ′-[2-[(Tertiary butoxycarbonyl) [(2R) -2- (6-chloro-3-pyridyl) -2-hydroxyethyl] amino] ethyl] -3- (cyclohexyloxy) -4- To a solution of methyl biphenylcarboxylate (1.43 g) in dichloromethane (25 ml), 3,4-dihydro-2H-pyran (0.64 ml) and pyridinium p-toluenesulfonate (118 mg) were added at room temperature and the mixture was The mixture was stirred for 2 days under a nitrogen atmosphere. The mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give a residue (2.34 g). To a solution of the above residue in methanol (8 ml) / tetrahydrofuran (8 ml) was added aqueous sodium hydroxide (1N, 8 ml) at room temperature and the mixture was stirred at room temperature overnight. The mixed solution was acidified with aqueous hydrochloric acid (1N), poured into water, and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/4), and 4 ′-[2-[(tertiary butoxycarbonyl) [(2R) -2- (6-chloro-3- Pyridyl) -2- (tetrahydro-2H-pyran-2-yloxy) ethyl] amino] ethyl] -3- (cyclohexyloxy) -4-biphenylcarboxylic acid (1.42 g) was obtained.
(-) ESI-MS (m / z): 677 (MH) -

製造例６９
４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−フェニル−２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エチル］アミノ］エチル］−３−イソプロポキシ−４−ビフェニルカルボン酸（２２４ｍｇ）のＮ，Ｎ−ジメチルホルムアミド（２ｍｌ）中の溶液に、１，１’カルボニルジイミダゾール（７２ｍｇ）を室温で加え、混合物を同温で１時間攪拌した。１−ペンタンスルホンアミド（６７ｍｇ）と１，８−ジアザビシクロ［５．４．０］−７−ウンデセン（０．０６７ｍｌ）を混合物に室温で加えた。混合物を７０℃で４時間攪拌した。室温まで冷却後、混合物を酢酸エチルで希釈し、塩酸水溶液（０．５Ｎ）と食塩水で洗浄し、硫酸ナトリウムで乾燥後、溶媒を減圧留去して、残留物（４０３ｍｇ）を得た。上記残留物のメタノール（２ｍｌ）中の溶液に、４−メチルベンゼンスルホン酸を室温で加え、混合物を同温で２日間攪拌し、混合物を酢酸エチルで希釈し、水と食塩水で洗浄し、硫酸ナトリウムで乾燥後、溶媒を減圧留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝７／３）で精製して、［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］［２−［３’−イソプロポキシ−４’−［［（ペンチルスルホニル）アミノ］カルボニル］−４−ビフェニリル］エチル］カルバミン酸第三級ブチル（１７９ｍｇ）を得た。
(+)ESI-MS (m/z): 675 (M+Na)+ Production Example 69
4 ′-[2-[(Tertiary butoxycarbonyl) [(2R) -2-phenyl-2- (tetrahydro-2H-pyran-2-yloxy) ethyl] amino] ethyl] -3-isopropoxy-4- To a solution of biphenylcarboxylic acid (224 mg) in N, N-dimethylformamide (2 ml) was added 1,1′carbonyldiimidazole (72 mg) at room temperature and the mixture was stirred at the same temperature for 1 hour. 1-Pentanesulfonamide (67 mg) and 1,8-diazabicyclo [5.4.0] -7-undecene (0.067 ml) were added to the mixture at room temperature. The mixture was stirred at 70 ° C. for 4 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with aqueous hydrochloric acid (0.5N) and brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give a residue (403 mg). To a solution of the above residue in methanol (2 ml) was added 4-methylbenzenesulfonic acid at room temperature, the mixture was stirred at the same temperature for 2 days, the mixture was diluted with ethyl acetate, washed with water and brine, After drying with sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 7/3) to give [(2R) -2-hydroxy-2-phenylethyl] [2- [3′-isopropoxy-4 ′-[ [(Pentylsulfonyl) amino] carbonyl] -4-biphenylyl] ethyl] tertiary butyl carbamate (179 mg) was obtained.
(+) ESI-MS (m / z): 675 (M + Na) +

製造例７０
下記の化合物を製造例６９と同様の方法にしたがって得た。
（１） ［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］［２−［４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−３’−イソプロポキシ−４−ビフェニリル］エチル］カルバミン酸第三級ブチル
(+)ESI-MS (m/z): 663 (M+Na)+ Production Example 70
The following compound was obtained in the same manner as in Production Example 69.
(1) [(2R) -2-hydroxy-2-phenylethyl] [2- [4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -3′-isopropoxy-4-biphenylyl] Ethyl] tertiary butyl carbamate
(+) ESI-MS (m / z): 663 (M + Na) +

（２） ［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］［２−［４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−３’−（イソプロピルチオ）−４−ビフェニリル］エチル］カルバミン酸第三級ブチル
(+)ESI-MS (m/z): 679 (M+Na)+ (2) [(2R) -2-hydroxy-2-phenylethyl] [2- [4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -3 ′-(isopropylthio) -4- Biphenylyl] ethyl] tertiary butyl carbamate
(+) ESI-MS (m / z): 679 (M + Na) +

（３） ［２−［３’−（シクロヘキシルオキシ）−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］エチル］［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］カルバミン酸第三級ブチル
(+)ESI-MS (m/z): 703 (M+Na)+ (3) [2- [3 ′-(Cyclohexyloxy) -4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -4-biphenylyl] ethyl] [(2R) -2-hydroxy-2 -Phenylethyl] tertiary butyl carbamate
(+) ESI-MS (m / z): 703 (M + Na) +

（４） ［（２Ｒ）−２−（６−クロロ−３−ピリジル）−２−ヒドロキシエチル］［２−［３’−（シクロヘキシルオキシ）−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］エチル］カルバミン酸第三級ブチル
(+)ESI-MS (m/z): 716 (M+H)+ (4) [(2R) -2- (6-Chloro-3-pyridyl) -2-hydroxyethyl] [2- [3 ′-(cyclohexyloxy) -4 ′-[[[(3-hydroxypropyl) sulfonyl] ] Amino] carbonyl] -4-biphenylyl] ethyl] tertiary butyl carbamate
(+) ESI-MS (m / z): 716 (M + H) +

（５） ［（２Ｒ）−２−（６−クロロ−３−ピリジル）−２−ヒドロキシエチル］［２−［３’−（シクロヘキシルオキシ）−４’−［［［（２−メトキシエチル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］エチル］カルバミン酸第三級ブチル
(+)ESI-MS (m/z): 716 (M+H)+ (5) [(2R) -2- (6-Chloro-3-pyridyl) -2-hydroxyethyl] [2- [3 ′-(cyclohexyloxy) -4 ′-[[[(2-methoxyethyl) sulfonyl] ] Amino] carbonyl] -4-biphenylyl] ethyl] tertiary butyl carbamate
(+) ESI-MS (m / z): 716 (M + H) +

製造例７１
４’−［２−［（第三級ブトキシカルボニル）アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニルカルボン酸メチル（１．５２ｇ）の１，４−ジオキサン（６ｍｌ）中の溶液に、塩酸／１，４−ジオキサン溶液（４Ｎ、８ｍｌ）を室温で加え、混合物を一夜攪拌した。混合物から溶媒を減圧留去した。残留物をクロロホルム／メタノール（５／１、８０ｍｌ）に溶解した。溶液を重炭酸ナトリウム水溶液（８０ｍｌ）と食塩水で洗浄し、硫酸ナトリウムで乾燥後、溶媒を減圧留去した。上記残留物（１．１８ｇ）とＮ，Ｎ’−ビス（トリメチルシリル）ウレア（０．８５ｇ）のジメチルスルホキシド（６ｍｌ）中の混合物を窒素雰囲気下に６５℃で攪拌した。１時間攪拌後、２−クロロ−５−［（２Ｒ）−２−オキシラニル］ピリジン（０．６５ｇ）を混合物に加えた。混合物を６５℃で４０時間攪拌した。濃塩酸水溶液（０．４ｍｌ）を混合物に約０℃で加えた。混合物を室温で３０分間攪拌した。重炭酸ナトリウム水溶液（４０ｍｌ）を混合物に加えた。混合物をクロロホルムで抽出し、硫酸ナトリウムで乾燥後、溶媒を減圧留去した。上記残留物（２．３ｇ）と二炭酸ジ第三級ブチル（１．３ｇ）のテトラヒドロフラン（５ｍｌ）中の混合物を一夜攪拌した。混合物を水に注ぎ、酢酸エチルで抽出し、硫酸ナトリウムで乾燥後、溶媒を減圧留去した。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝５／５）で精製して、４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（６−クロロ−３−ピリジル）−２−ヒドロキシエチル）アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニルカルボン酸メチル（１．４４ｇ）を得た。
(+)ESI-MS (m/z): 609 (M+H)+ Production Example 71
To a solution of methyl 4 ′-[2-[(tertiarybutoxycarbonyl) amino] ethyl] -3- (cyclohexyloxy) -4-biphenylcarboxylate (1.52 g) in 1,4-dioxane (6 ml). Hydrochloric acid / 1,4-dioxane solution (4N, 8 ml) was added at room temperature and the mixture was stirred overnight. The solvent was distilled off from the mixture under reduced pressure. The residue was dissolved in chloroform / methanol (5/1, 80 ml). The solution was washed with aqueous sodium bicarbonate solution (80 ml) and brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. A mixture of the above residue (1.18 g) and N, N′-bis (trimethylsilyl) urea (0.85 g) in dimethyl sulfoxide (6 ml) was stirred at 65 ° C. under a nitrogen atmosphere. After stirring for 1 hour, 2-chloro-5-[(2R) -2-oxiranyl] pyridine (0.65 g) was added to the mixture. The mixture was stirred at 65 ° C. for 40 hours. Concentrated aqueous hydrochloric acid (0.4 ml) was added to the mixture at about 0 ° C. The mixture was stirred at room temperature for 30 minutes. Aqueous sodium bicarbonate (40 ml) was added to the mixture. The mixture was extracted with chloroform and dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. A mixture of the above residue (2.3 g) and di-tert-butyl dicarbonate (1.3 g) in tetrahydrofuran (5 ml) was stirred overnight. The mixture was poured into water, extracted with ethyl acetate, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/5), and 4 ′-[2-[(tertiary butoxycarbonyl) [(2R) -2- (6-chloro-3- Methyl pyridyl) -2-hydroxyethyl) amino] ethyl] -3- (cyclohexyloxy) -4-biphenylcarboxylate (1.44 g) was obtained.
(+) ESI-MS (m / z): 609 (M + H) +

製造例７２
［（２Ｒ）−２−（６−クロロ−３−ピリジル）−２−ヒドロキシエチル］［２−［３’−（シクロヘキシルオキシ）−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］エチル］カルバミン酸第三級ブチル（１４５ｍｇ）、蟻酸アンモニウム（１２８ｍｇ）とパラジウム炭粉末（５０ｍｇ）のメタノール（２ｍｌ）と水（０．２ｍｌ）中の混合物を５０分間還流した。触媒を濾去し、濾液から溶媒を減圧留去した。残留物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝９４／６）で精製して、［２−［３’−（シクロヘキシルオキシ）−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］エチル］［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］カルバミン酸第三級ブチル（１１７ｍｇ）を得た。
(+)ESI-MS (m/z): 682 (M+H)+ Production Example 72
[(2R) -2- (6-chloro-3-pyridyl) -2-hydroxyethyl] [2- [3 ′-(cyclohexyloxy) -4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] [Carbonyl] -4-biphenylyl] ethyl] tertiary butyl carbamate (145 mg), ammonium formate (128 mg) and palladium on charcoal powder (50 mg) in methanol (2 ml) and water (0.2 ml) refluxed for 50 minutes. did. The catalyst was removed by filtration, and the solvent was distilled off from the filtrate under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol = 94/6) to obtain [2- [3 ′-(cyclohexyloxy) -4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl. ] -4-biphenylyl] ethyl] [(2R) -2-hydroxy-2- (3-pyridyl) ethyl] tertiary butyl carbamate (117 mg) was obtained.
(+) ESI-MS (m / z): 682 (M + H) +

製造例７３
下記の化合物を製造例７２と同様の方法にしたがって得た。 Production Example 73
The following compound was obtained according to the same method as in Production Example 72.

［２−［３’−（シクロヘキシルオキシ）−４’−［［［（２−メトキシエチル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］エチル］［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］カルバミン酸第三級ブチル
(+)ESI-MS (m/z): 682 (M+H)+ [2- [3 ′-(cyclohexyloxy) -4 ′-[[[(2-methoxyethyl) sulfonyl] amino] carbonyl] -4-biphenylyl] ethyl] [(2R) -2-hydroxy-2- (3 -Pyridyl) ethyl] tertiary butyl carbamate
(+) ESI-MS (m / z): 682 (M + H) +

実施例３６
［２−［３’−（イソプロピルチオ）−４’−［［（３−ピリジルスルホニル）アミノ］カルボニル］−４−ビフェニリル］エチル］［（２Ｒ）−２−フェニル−２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エチル］カルバミン酸第三級ブチル（４１１ｍｇ）と塩化水素／メタノール（１０％、８．２２ｍｌ）の混合物を室温で一夜攪拌した。混合物から溶媒を留去し、エタノールから再結晶して、４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エチル］−３−（イソプロピルチオ）−Ｎ−（３−ピリジルスルホニル）−４−ビフェニルカルボキサミド二塩酸塩（２４２ｍｇ）を得た。
NMR (200 MHz, DMSO-d6, δ): 1.05 (6H, d, J=6.6Hz), 2.89-3.33 (6H, m), 3.33-3.46 (1H, m), 5.00 (1H, dd, J=2.7, 10.3Hz), 7.30-7.41 (7H, m), 7.54-7.64 (2H, m), 7.68-7.79 (4H, m), 8.41 (1H, dt, J=2.3, 4Hz), 8.94 (1H, dd, J=1.5, 5Hz), 8.93 (1H, br s), 9.15 (1H, d, J=1.5Hz), 9.33 (1H, br s)
(-)ESI-MS (m/z): 574 (M-H)- Example 36
[2- [3 ′-(Isopropylthio) -4 ′-[[(3-pyridylsulfonyl) amino] carbonyl] -4-biphenylyl] ethyl] [(2R) -2-phenyl-2- (tetrahydro-2H- A mixture of pyran-2-yloxy) ethyl] tertiary butyl carbamate (411 mg) and hydrogen chloride / methanol (10%, 8.22 ml) was stirred at room temperature overnight. The solvent was distilled off from the mixture, recrystallized from ethanol, and 4 ′-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethyl] -3- (isopropylthio) -N—. (3-Pyridylsulfonyl) -4-biphenylcarboxamide dihydrochloride (242 mg) was obtained.
NMR (200 MHz, DMSO-d 6 , δ): 1.05 (6H, d, J = 6.6Hz), 2.89-3.33 (6H, m), 3.33-3.46 (1H, m), 5.00 (1H, dd, J = 2.7, 10.3Hz), 7.30-7.41 (7H, m), 7.54-7.64 (2H, m), 7.68-7.79 (4H, m), 8.41 (1H, dt, J = 2.3, 4Hz), 8.94 (1H , dd, J = 1.5, 5Hz), 8.93 (1H, br s), 9.15 (1H, d, J = 1.5Hz), 9.33 (1H, br s)
(-) ESI-MS (m / z): 574 (MH) -

実施例３７〜実施例３９の下記の化合物を実施例３６と同様の方法にしたがって得た。
実施例３７
Ｎ−［（シアノメチル）スルホニル］−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エチル］−３−（イソプロピルチオ）−４−ビフェニル−カルボキサミド塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.27 (6H, d, J=6.5Hz), 3.05-3.24 (6H, m), 3.60-3.73 (1H, m), 4.86 (2H, s), 4.98 (1H, d, J=9.5Hz), 6.22 (1H, br s), 7.31-7.42 (7H, m), 7.52 (1H, d, J=8Hz), 7.62-7.63 (1H, m), 7.69-7.76 (3H, m), 8.85 (1H, br s), 9.06 (1H, br s)
(-)ESI-MS (m/z): 536 (M-H)- The following compounds of Examples 37 to 39 were obtained in the same manner as in Example 36.
Example 37
N-[(cyanomethyl) sulfonyl] -4 ′-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethyl] -3- (isopropylthio) -4-biphenyl-carboxamide hydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 1.27 (6H, d, J = 6.5Hz), 3.05-3.24 (6H, m), 3.60-3.73 (1H, m), 4.86 (2H, s), 4.98 (1H, d, J = 9.5Hz), 6.22 (1H, br s), 7.31-7.42 (7H, m), 7.52 (1H, d, J = 8Hz), 7.62-7.63 (1H, m), 7.69 -7.76 (3H, m), 8.85 (1H, br s), 9.06 (1H, br s)
(-) ESI-MS (m / z): 536 (MH) -

実施例３８
３−（シクロヘキシルオキシ）−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エチル］−Ｎ−（３−ピリジルスルホニル）−４−ビフェニルカルボキサミド三塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.31-1.67 (8H, m), 1.71-1.91 (2H, m), 3.02-3.50 (6H, m), 4.61-4.78 (1H, m), 5.34 (1H, d, J=5.6Hz), 7.29 (1H, d, J=8Hz), 7.36-7.40 (3H, m), 7.54 (1H, d, J=8Hz), 7.70 (2H, d, J=8Hz ), 7.74 (1H, dd, J=6.2, 10.5Hz), 8.08 (1H, dd, J=5.5, 8Hz), 8.41 (1H, dt, J=2.8, 3.8Hz), 8.60 (1H, d, J=8Hz), 8.88-8.94 (3H, m), 9.15 (1H, d, J=1.5Hz), 9.36 (2H, br s), 12.06 (1H, br s)
(-)ESI-MS (m/z): 599 (M-H)- Example 38
3- (Cyclohexyloxy) -4 '-[2-[[(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] ethyl] -N- (3-pyridylsulfonyl) -4-biphenylcarboxamide Trihydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 1.31-1.67 (8H, m), 1.71-1.91 (2H, m), 3.02-3.50 (6H, m), 4.61-4.78 (1H, m), 5.34 (1H, d, J = 5.6Hz), 7.29 (1H, d, J = 8Hz), 7.36-7.40 (3H, m), 7.54 (1H, d, J = 8Hz), 7.70 (2H, d, J = 8Hz), 7.74 (1H, dd, J = 6.2, 10.5Hz), 8.08 (1H, dd, J = 5.5, 8Hz), 8.41 (1H, dt, J = 2.8, 3.8Hz), 8.60 (1H, d, J = 8Hz), 8.88-8.94 (3H, m), 9.15 (1H, d, J = 1.5Hz), 9.36 (2H, br s), 12.06 (1H, br s)
(-) ESI-MS (m / z): 599 (MH) -

実施例３９
Ｎ−［（シアノメチル）スルホニル］−３−（シクロヘキシルオキシ）−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エチル］−４−ビフェニルカルボキサミド二塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.32-1.85 (8H, m), 1.86-2.02 (2H, m), 3.04-3.48 (6H, m), 4.63-4.91 (1H, m), 5.20-5.32 (3H, m), 7.34-7.42 (3H, m), 7.67 (1H, d, J=8Hz), 7.74 (2H, d, J=8Hz), 8.00 (1H, dd, J=5.5, 8Hz), 8.50 (1H, d, J=8.5Hz), 8.85 (1H, d, J=5.5Hz), 8.91 (1H, s), 9.28 (1H, br s), 9.39 (1H, br s)
(-)ESI-MS (m/z): 561 (M-H)- Example 39
N-[(cyanomethyl) sulfonyl] -3- (cyclohexyloxy) -4 '-[2-[[(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] ethyl] -4-biphenylcarboxamide Dihydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 1.32-1.85 (8H, m), 1.86-2.02 (2H, m), 3.04-3.48 (6H, m), 4.63-4.91 (1H, m), 5.20 -5.32 (3H, m), 7.34-7.42 (3H, m), 7.67 (1H, d, J = 8Hz), 7.74 (2H, d, J = 8Hz), 8.00 (1H, dd, J = 5.5, 8Hz) ), 8.50 (1H, d, J = 8.5Hz), 8.85 (1H, d, J = 5.5Hz), 8.91 (1H, s), 9.28 (1H, br s), 9.39 (1H, br s)
(-) ESI-MS (m / z): 561 (MH) -

実施例４０
４’−［［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］アミノ］−３−イソブトキシ−４−ビフェニルカルボン酸（６０．０ｍｇ）のＮ，Ｎ−ジメチルホルムアミド（０．４５０ｍｌ）中の溶液に、１，１’−カルボニルビス−１Ｈ−イミダゾール（１８．３ｍｇ）を加え、混合物を窒素雰囲気下に室温で１．５時間攪拌した。混合物に２，３，４，６，７，８，９，１０−オクタヒドロピリミド［１，２−ａ］アゼピン（０．０１８５ｍｌ）と酢酸３−（アミノスルホニル）プロピル（２２．４ｍｇ）のＮ，Ｎ−ジメチルホルムアミド（０．３００ｍｌ）中の溶液を加え、混合物を室温で２日間攪拌した。反応混合物を１２０℃に加温し、同温で２時間攪拌した。室温まで冷却後、反応混合物を酢酸エチルで抽出し、水と食塩水で洗浄し、硫酸マグネシウムで乾燥した。濾過後、溶媒を留去して、粗製生成物を得て、これをシリカゲルカラムクロマトグラフィー（溶離溶媒：ヘキサン／酢酸エチル＝１／３〜１／１）で精製して、酢酸３−［［［［４’−［［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］アミノ］−３−イソブトキシ−４−ビフェニリル］カルボニル］アミノ］スルホニル］プロピル（３４．１ｍｇ）を黄色ペースト状物として得た。
(-)ESI-MS (m/z): 744 (M-H)- Example 40
4 ′-[[2-[(tertiary butoxycarbonyl) [(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] -3-isobutoxy-4-biphenylcarboxylic acid ( To a solution of 60.0 mg) in N, N-dimethylformamide (0.450 ml) was added 1,1′-carbonylbis-1H-imidazole (18.3 mg) and the mixture was 1. Stir for 5 hours. To the mixture was 2,3,4,6,7,8,9,10-octahydropyrimido [1,2-a] azepine (0.0185 ml) and 3- (aminosulfonyl) propyl acetate (22.4 mg). A solution in N, N-dimethylformamide (0.300 ml) was added and the mixture was stirred at room temperature for 2 days. The reaction mixture was warmed to 120 ° C. and stirred at the same temperature for 2 hours. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate, washed with water and brine, and dried over magnesium sulfate. After filtration, the solvent was distilled off to obtain a crude product, which was purified by silica gel column chromatography (eluent: hexane / ethyl acetate = 1/3 to 1/1) to give acetic acid 3-[[ [[4 '-[[2-[(Tertiary butoxycarbonyl) [(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] -3-isobutoxy-4-biphenylyl] Carbonyl] amino] sulfonyl] propyl (34.1 mg) was obtained as a yellow paste.
(-) ESI-MS (m / z): 744 (MH) -

実施例４１
酢酸３−［［［［４’−［［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］アミノ］−３−イソブトキシ−４−ビフェニリル］カルボニル］アミノ］スルホニル］プロピル（３４．０ｍｇ）のメタノール（０．３４０ｍｌ）とテトラヒドロフラン（０．１７０ｍｌ）中の溶液に、１Ｎ水酸化ナトリウム水溶液（０．２２８ｍｌ）を加え、混合物を室温で１時間攪拌した。反応混合物を酢酸エチルで抽出し、水と食塩水で洗浄し、硫酸マグネシウムで乾燥した。溶媒を減圧濃縮した。生じた残留物の１，４−ジオキサン（０．３４０ｍｌ）中の溶液に、４Ｎ塩化水素／１，４−ジオキサン（０．３４０ｍｌ）を加え、混合物を室温で一夜攪拌した。溶媒を減圧濃縮し、残留物に酢酸エチルを加えた。沈殿物を濾取し、真空乾燥して、４’−［［２−［［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］アミノ］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−３−イソブトキシ−４−ビフェニルカルボキサミド二塩酸塩（２４．８ｍｇ）を黄色粉末として得た。
NMR (200 MHz, DMSO-d6, δ): 1.05 (6H, d, J=7Hz), 1.79-1.93 (2H, m), 2.02-2.19 (1H, m), 2.99-3.35 (4H, m), 3.61-3.44 (6H, m), 4.01-4.06 (2H, m), 4.98-5.05 (1H, m), 6.75 (2H, d, J=8.5Hz), 7.28-7.49 (6H, m), 7.57-7.71 (3H, m), 8.85 (1H, br s), 9.18 (1H, br s), 10.99 (1H, s)
(-)ESI-MS (m/z): 603 (M-H)- Example 41
Acetic acid 3-[[[[4 '-[[2-[(tertiarybutoxycarbonyl) [(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] -3-isobutoxy To a solution of -4-biphenylyl] carbonyl] amino] sulfonyl] propyl (34.0 mg) in methanol (0.340 ml) and tetrahydrofuran (0.170 ml) was added 1N aqueous sodium hydroxide (0.228 ml) and the mixture Was stirred at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate, washed with water and brine, and dried over magnesium sulfate. The solvent was concentrated under reduced pressure. To a solution of the resulting residue in 1,4-dioxane (0.340 ml) was added 4N hydrogen chloride / 1,4-dioxane (0.340 ml) and the mixture was stirred at room temperature overnight. The solvent was concentrated under reduced pressure, and ethyl acetate was added to the residue. The precipitate was collected by filtration, dried in vacuo and 4 '-[[2-[[(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] -N-[(3 -Hydroxypropyl) sulfonyl] -3-isobutoxy-4-biphenylcarboxamide dihydrochloride (24.8 mg) was obtained as a yellow powder.
NMR (200 MHz, DMSO-d 6 , δ): 1.05 (6H, d, J = 7Hz), 1.79-1.93 (2H, m), 2.02-2.19 (1H, m), 2.99-3.35 (4H, m) , 3.61-3.44 (6H, m), 4.01-4.06 (2H, m), 4.98-5.05 (1H, m), 6.75 (2H, d, J = 8.5Hz), 7.28-7.49 (6H, m), 7.57 -7.71 (3H, m), 8.85 (1H, br s), 9.18 (1H, br s), 10.99 (1H, s)
(-) ESI-MS (m / z): 603 (MH) -

実施例４２
下記の化合物を実施例４０と同様の方法にしたがって得た。 Example 42
The following compound was obtained according to the same method as in Example 40.

酢酸３−［［［［４’−［［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］アミノ］−３−（シクロヘキシルオキシ）−４−ビフェニリル］カルボニル］アミノ］スルホニル］プロピル
(-)ESI-MS (m/z): 770 (M-H)- Acetic acid 3-[[[[4 ′-[[2-[(tertiarybutoxycarbonyl) [(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] -3- ( (Cyclohexyloxy) -4-biphenylyl] carbonyl] amino] sulfonyl] propyl
(-) ESI-MS (m / z): 770 (MH) -

実施例４３
下記の化合物を実施例４１と同様の方法にしたがって得た。 Example 43
The following compound was obtained in the same manner as in Example 41.

４’−［［２−［［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］アミノ］−３−（シクロヘキシルオキシ）−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４−ビフェニルカルボキサミド二塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.29-1.64 (6H, m), 1.68-1.78 (2H, m), 1.82-1.91 (2H, m), 1.93-2.01 (2H, m), 3.02-3.31 (4H, m), 3.48-3.58 (6H, m), 4.80-4.86 (1H, m), 5.01-5.04 (1H, m), 6.76 (2H, d, J=8.8Hz), 7.29-7.48 (6H, m), 7.58 (2H, d, J=8.8Hz), 7.74 (1H, d, J=8.4Hz), 8.87 (1H, br s), 9.24 (1H, br s), 10.97 (1H, s)
(-)ESI-MS (m/z): 628 (M-H)- 4 ′-[[2-[[(2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] -3- (cyclohexyloxy) -N-[(3-hydroxypropyl) sulfonyl ] -4-Biphenylcarboxamide dihydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 1.29-1.64 (6H, m), 1.68-1.78 (2H, m), 1.82-1.91 (2H, m), 1.93-2.01 (2H, m), 3.02 -3.31 (4H, m), 3.48-3.58 (6H, m), 4.80-4.86 (1H, m), 5.01-5.04 (1H, m), 6.76 (2H, d, J = 8.8Hz), 7.29-7.48 (6H, m), 7.58 (2H, d, J = 8.8Hz), 7.74 (1H, d, J = 8.4Hz), 8.87 (1H, br s), 9.24 (1H, br s), 10.97 (1H, s)
(-) ESI-MS (m / z): 628 (MH) -

実施例４４
下記の化合物を製造例６４と同様の方法にしたがって得た。 Example 44
The following compound was obtained according to the same method as in Production Example 64.

６−［４−［２−［［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］フェニル］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−１−イソプロピル−１Ｈ−インドール−３−カルボキサミド塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.52 (6H, d, J=6.5Hz), 1.75-1.95 (2H, m), 2.95-3.65 (10H, m), 4.90-5.05 (2H, m), 7.30-7.60 (7H, m), 7.76 (2H, d, J=8.2Hz), 7.90 (1H, s), 8.18 (1H, d, J=8.4Hz), 8.65 (1H, s)
(-)ESI-MS (m/z): 596 (M-2HCl-H)- 6- [4- [2-[[(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] phenyl] -N-[(3-hydroxypropyl) sulfonyl] -1-isopropyl- 1H-indole-3-carboxamide hydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 1.52 (6H, d, J = 6.5Hz), 1.75-1.95 (2H, m), 2.95-3.65 (10H, m), 4.90-5.05 (2H, m ), 7.30-7.60 (7H, m), 7.76 (2H, d, J = 8.2Hz), 7.90 (1H, s), 8.18 (1H, d, J = 8.4Hz), 8.65 (1H, s)
(-) ESI-MS (m / z): 596 (M-2HCl-H) -

実施例４５
３−［［［［４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−［［第三級ブチル（ジメチル）シリル］オキシ］−２−（３−ピリジル）エチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニリル］カルボニル］アミノ］スルホニル］プロピオン酸（４９．７ｍｇ）に、４Ｎ塩化水素／１，４−ジオキサン（１．５ｍｌ）を加えた。室温で１２時間攪拌後、混合物から溶媒を留去して、３−［［［［３−（シクロヘキシルオキシ）−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エチル］−４−ビフェニリル］カルボニル］アミノ］スルホニル］プロパン酸二塩酸塩（４１．０ｍｇ）を得た。
NMR (200 MHz, DMSO-d6, δ): 1.23-1.70 (10H, m), 1.90-1.98 (2H, m), 2.71-2.79 (2H, m), 3.07-3.36 (4H, m), 3.56-3.79 (2H, m), 5.20-5.29 (1H, m), 5.70-5.76 (1H, m), 6.30 (1H, br s), 7.16-7.41 (4H, m), 7.63-7.75 (3H, m), 7.90-7.97 (1H, m), 8.41-8.46 (1H, m), 8.84 (2H, d, J=16Hz), 9.20-9.34 (2H, m)
(-)ESI-MS (m/z): 594 (M-2HCl-H)- Example 45
3-[[[[4 '-[2-[(Tertiary butoxycarbonyl) [(2R) -2-[[Tertiary butyl (dimethyl) silyl] oxy] -2- (3-pyridyl) ethyl] To amino] ethyl] -3- (cyclohexyloxy) -4-biphenylyl] carbonyl] amino] sulfonyl] propionic acid (49.7 mg) was added 4N hydrogen chloride / 1,4-dioxane (1.5 ml). After stirring at room temperature for 12 hours, the solvent was distilled off from the mixture, and 3-[[[[3- (cyclohexyloxy) -4 ′-[2-[[(2R) -2-hydroxy-2- (3- Pyridyl) ethyl] amino] ethyl] -4-biphenylyl] carbonyl] amino] sulfonyl] propanoic acid dihydrochloride (41.0 mg) was obtained.
NMR (200 MHz, DMSO-d 6 , δ): 1.23-1.70 (10H, m), 1.90-1.98 (2H, m), 2.71-2.79 (2H, m), 3.07-3.36 (4H, m), 3.56 -3.79 (2H, m), 5.20-5.29 (1H, m), 5.70-5.76 (1H, m), 6.30 (1H, br s), 7.16-7.41 (4H, m), 7.63-7.75 (3H, m ), 7.90-7.97 (1H, m), 8.41-8.46 (1H, m), 8.84 (2H, d, J = 16Hz), 9.20-9.34 (2H, m)
(-) ESI-MS (m / z): 594 (M-2HCl-H) -

実施例４６〜実施例４９の下記の化合物を実施例４５と同様の方法にしたがって得た。
実施例４６
３−（シクロヘキシルオキシ）−Ｎ−［（３−ヒドロキシ−３−メチルブチル）スルホニル］−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］−アミノ］エチル］−４−ビフェニルカルボキサミド二塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.12 (6H, s), 1.12-1.92 (10H, m), 1.92-1.98 (2H, m), 3.07-3.59 (8H, m), 4.78-4.83 (1H, m), 5.20-5.28 (1H, m), 7.33-7.44 (4H, m), 7.72-7.76 (3H, m), 7.88-7.95 (1H, m), 8.30-8.42 (1H, m), 8.75-8.86 (2H, m)
(-)ESI-MS (m/z): 608 (M-H)- The following compounds of Examples 46 to 49 were obtained in the same manner as in Example 45.
Example 46
3- (Cyclohexyloxy) -N-[(3-hydroxy-3-methylbutyl) sulfonyl] -4 ′-[2-[[(2R) -2-hydroxy-2- (3-pyridyl) ethyl] -amino] Ethyl] -4-biphenylcarboxamide dihydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 1.12 (6H, s), 1.12-1.92 (10H, m), 1.92-1.98 (2H, m), 3.07-3.59 (8H, m), 4.78-4.83 (1H, m), 5.20-5.28 (1H, m), 7.33-7.44 (4H, m), 7.72-7.76 (3H, m), 7.88-7.95 (1H, m), 8.30-8.42 (1H, m) , 8.75-8.86 (2H, m)
(-) ESI-MS (m / z): 608 (MH) -

実施例４７
Ｎ−［（２−アミノ−２−オキソエチル）スルホニル］−３−（シクロヘキシルオキシ）−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エチル］−４−ビフェニルカルボキサミド二塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.39-1.72 (10H, m), 2.99 (2H, s), 3.00-3.50 (6H, m), 4.70-4.90 (1H, m), 5.25-5.30 (1H, m), 7.23-7.44 (4H, m), 7.73-7.97 (4H, m), 8.40-8.45 (1H, m), 8.81-8.88 (2H, m), 9.24-9.40 (2H, m)
(-)ESI-MS (m/z): 579 (M-H)- Example 47
N-[(2-amino-2-oxoethyl) sulfonyl] -3- (cyclohexyloxy) -4 '-[2-[[(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] ethyl ] -4-Biphenylcarboxamide dihydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 1.39-1.72 (10H, m), 2.99 (2H, s), 3.00-3.50 (6H, m), 4.70-4.90 (1H, m), 5.25-5.30 (1H, m), 7.23-7.44 (4H, m), 7.73-7.97 (4H, m), 8.40-8.45 (1H, m), 8.81-8.88 (2H, m), 9.24-9.40 (2H, m)
(-) ESI-MS (m / z): 579 (MH) -

実施例４８
３−（シクロヘキシルオキシ）−Ｎ−［（４−ヒドロキシブチル）スルホニル］−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エチル］−４−ビフェニルカルボキサミド二塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.23-1.91 (14H, m), 3.11-3.80 (10H, m), 4.78-4.82 (1H, m), 5.23-5.27 (1H, m), 7.30-7.42 (4H, m), 7.71-7.75 (3H, m), 7.86-7.93 (1H, m), 8.34-8.39 (1H, m), 8.78-8.86 (2H, m), 9.12-9.29 (2H, m), 11.17 (1H, s)
(-)ESI-MS (m/z): 594 (M-H)- Example 48
3- (Cyclohexyloxy) -N-[(4-hydroxybutyl) sulfonyl] -4 ′-[2-[[(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] ethyl] -4 -Biphenylcarboxamide dihydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 1.23-1.91 (14H, m), 3.11-3.80 (10H, m), 4.78-4.82 (1H, m), 5.23-5.27 (1H, m), 7.30 -7.42 (4H, m), 7.71-7.75 (3H, m), 7.86-7.93 (1H, m), 8.34-8.39 (1H, m), 8.78-8.86 (2H, m), 9.12-9.29 (2H, m), 11.17 (1H, s)
(-) ESI-MS (m / z): 594 (MH) -

実施例４９
Ｎ−［（２−アミノ−２−オキソエチル）スルホニル］−４’−［２−［［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニルカルボキサミド塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.02-1.94 (10H, m), 3.05-3.33 (6H, m), 4.35 (2H, s), 4.81-4.83 (1H, m), 4.98-5.03 (1H, m), 6.36 (1H, d, J=2Hz), 7.36-7.48 (7H, m), 7.73-7.84 (4H, m), 8.90-9.13 (2H, m), 11.2 (1H, br s)
(+)ESI-MS (m/z): 594 (M+H)+ Example 49
N-[(2-amino-2-oxoethyl) sulfonyl] -4 '-[2-[[(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] ethyl] -3- (cyclohexyloxy ) -4-Biphenylcarboxamide hydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 1.02-1.94 (10H, m), 3.05-3.33 (6H, m), 4.35 (2H, s), 4.81-4.83 (1H, m), 4.98-5.03 (1H, m), 6.36 (1H, d, J = 2Hz), 7.36-7.48 (7H, m), 7.73-7.84 (4H, m), 8.90-9.13 (2H, m), 11.2 (1H, br s )
(+) ESI-MS (m / z): 594 (M + H) +

実施例５０
４’−［２−［（第三級ブトキシカルボニル）［（２Ｒ）−２−（６−クロロ−３−ピリジル）−２−（テトラヒドロ−２Ｈ−ピラン−２−イルオキシ）エチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−４−ビフェニルカルボン酸（１８０ｍｇ）のＮ，Ｎ−ジメチルホルムアミド（２ｍｌ）中の混合物に、１，１’−カルボニルジイミダゾール（５１．６ｍｇ）を室温で加え、混合物を同温で１時間攪拌した。Ｎ−エチルスルファミド（４６．１ｍｇ）と１，８−ジアザビシクロ［５．４．０］−７−ウンデセン（０．０５６ｍｌ）を混合物に室温で加えた。混合物を室温で０．５時間、１２０℃に１６時間攪拌した。混合物を酢酸エチルで希釈し、水、０．５Ｎ塩酸と食塩水で洗浄し、硫酸ナトリウムで乾燥後、溶媒を減圧留去して、残留物（２２０ｍｇ）を得た。上記残留物のメタノール（３ｍｌ）中の混合物に、４−メチルベンゼンスルホン酸（２２ｍｇ）を室温で加え、混合物を室温で一夜攪拌した。混合物を酢酸エチルで希釈し、水と食塩水で洗浄し、硫酸ナトリウムで乾燥後、溶媒を減圧留去して、残留物を得た。残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝５０／５０）で精製して、残留物（１３５ｍｇ）を得た。上記残留物と蟻酸アンモニウム（１１８ｍｇ）のメタノール（２ｍｌ）と水（０．２ｍｌ）中の混合物に、１０％パラジウム炭（５０％湿潤、２５ｍｇ）を窒素雰囲気下に加えた。混合物を３０分間還流した。混合物をセライトパッドで濾過し、濾液から溶媒を減圧留去した。残留物をカラムクロマトグラフィー（クロロホルム／メタノール＝９５／５）で精製して、［２−［３’−（シクロヘキシルオキシ）−４’−［［［（エチルアミノ）スルホニル］アミノ］カルボニル］−４−ビフェニリル］エチル］［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］カルバミン酸第三級ブチル（１３２ｍｇ）を得た。
(-)ESI-MS (m/z): 665 (M-H)- Example 50
4 ′-[2-[(Tertiary butoxycarbonyl) [(2R) -2- (6-chloro-3-pyridyl) -2- (tetrahydro-2H-pyran-2-yloxy) ethyl] amino] ethyl] To a mixture of -3- (cyclohexyloxy) -4-biphenylcarboxylic acid (180 mg) in N, N-dimethylformamide (2 ml) was added 1,1′-carbonyldiimidazole (51.6 mg) at room temperature and the mixture Was stirred at the same temperature for 1 hour. N-ethylsulfamide (46.1 mg) and 1,8-diazabicyclo [5.4.0] -7-undecene (0.056 ml) were added to the mixture at room temperature. The mixture was stirred at room temperature for 0.5 hours and at 120 ° C. for 16 hours. The mixture was diluted with ethyl acetate, washed with water, 0.5N hydrochloric acid and brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give a residue (220 mg). To a mixture of the above residue in methanol (3 ml) was added 4-methylbenzenesulfonic acid (22 mg) at room temperature and the mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 50/50) to give a residue (135 mg). To a mixture of the above residue and ammonium formate (118 mg) in methanol (2 ml) and water (0.2 ml) was added 10% palladium on charcoal (50% wet, 25 mg) under a nitrogen atmosphere. The mixture was refluxed for 30 minutes. The mixture was filtered through a celite pad, and the solvent was distilled off from the filtrate under reduced pressure. The residue was purified by column chromatography (chloroform / methanol = 95/5) to give [2- [3 ′-(cyclohexyloxy) -4 ′-[[[(ethylamino) sulfonyl] amino] carbonyl] -4. -Biphenylyl] ethyl] [(2R) -2-hydroxy-2- (3-pyridyl) ethyl] tertiary butyl carbamate (132 mg) was obtained.
(-) ESI-MS (m / z): 665 (MH) -

実施例５１
下記の化合物を実施例４１と同様の方法にしたがって得た。 Example 51
The following compound was obtained in the same manner as in Example 41.

４’−［２−［［（２Ｒ）−２−（６−クロロ−３−ピリジル）−２−ヒドロキシエチル］アミノ］エチル］−３−（シクロヘキシルオキシ）−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４−ビフェニルカルボキサミド塩酸塩
NMR (200 MHz, DMSO-d6, δ): 1.29-2.03 (12H, m), 3.02-3.33 (6H, m), 3.48-3.60 (4H, m), 4.02-4.38 (2H, m), 4.75-4.87 (1H, m), 5.13 (1H, dd, J=3.0, 9.5Hz), 7.33-7.42 (4H, m), 7.57 ( H, d, J=8.0Hz ), 7.71-7.76 (3H, m), 7.89 (1H, d, J=2.5Hz), 8.46 (1H, d, J=2.5Hz), 9.09 (1H, br s), 9.35 (1H, br s), 11.18 (1H, s)
(-)ESI-MS (m/z): 614 (M-H)- 4 ′-[2-[[(2R) -2- (6-Chloro-3-pyridyl) -2-hydroxyethyl] amino] ethyl] -3- (cyclohexyloxy) -N-[(3-hydroxypropyl) Sulfonyl] -4-biphenylcarboxamide hydrochloride
NMR (200 MHz, DMSO-d 6 , δ): 1.29-2.03 (12H, m), 3.02-3.33 (6H, m), 3.48-3.60 (4H, m), 4.02-4.38 (2H, m), 4.75 -4.87 (1H, m), 5.13 (1H, dd, J = 3.0, 9.5Hz), 7.33-7.42 (4H, m), 7.57 (H, d, J = 8.0Hz), 7.71-7.76 (3H, m ), 7.89 (1H, d, J = 2.5Hz), 8.46 (1H, d, J = 2.5Hz), 9.09 (1H, br s), 9.35 (1H, br s), 11.18 (1H, s)
(-) ESI-MS (m / z): 614 (MH) -

実施例５２
［２−［３’−（シクロヘキシルオキシ）−４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］エチル］［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］カルバミン酸第三級ブチル（１１０ｍｇ）の１，４−ジオキサン（１．５ｍｌ）中の溶液に、塩化水素／１，４−ジオキサン（４Ｎ、１．５ｍｌ）を室温で加え、混合物を同温で一夜攪拌した。混合物から溶媒を減圧留去して、３−（シクロヘキシルオキシ）−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エチル］−４−ビフェニルカルボキサミド二塩酸塩（１０５ｍｇ）を白色固形物として得た。
NMR (200 MHz, DMSO-d6, δ): 1.35-2.02 (12H, m), 3.05-3.39 (6H, m), 3.48-3.60 (4H, m), 4.75-4.87 (1H, m), 5.27-5.35 (1H, m), 7.33-7.44 (4H, m), 7.71-7.75 (3H, m), 7.98 (1H, dd, J=5.5, 8.5Hz), 8.49 (1H, d, J=8.5Hz), 8.83-8.91 (2H, m), 9.30 (1H, br s), 9.41 (1H, br s), 11.18 (1H, s)
(-)ESI-MS (m/z): 580 (M-H)- Example 52
[2- [3 ′-(cyclohexyloxy) -4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -4-biphenylyl] ethyl] [(2R) -2-hydroxy-2- (3 -Pyridyl) ethyl] tertiary butyl carbamate (110 mg) in 1,4-dioxane (1.5 ml) was added hydrogen chloride / 1,4-dioxane (4N, 1.5 ml) at room temperature, The mixture was stirred overnight at the same temperature. The solvent was removed from the mixture under reduced pressure, and 3- (cyclohexyloxy) -N-[(3-hydroxypropyl) sulfonyl] -4 ′-[2-[[(2R) -2-hydroxy-2- (3- Pyridyl) ethyl] amino] ethyl] -4-biphenylcarboxamide dihydrochloride (105 mg) was obtained as a white solid.
NMR (200 MHz, DMSO-d 6 , δ): 1.35-2.02 (12H, m), 3.05-3.39 (6H, m), 3.48-3.60 (4H, m), 4.75-4.87 (1H, m), 5.27 -5.35 (1H, m), 7.33-7.44 (4H, m), 7.71-7.75 (3H, m), 7.98 (1H, dd, J = 5.5, 8.5Hz), 8.49 (1H, d, J = 8.5Hz ), 8.83-8.91 (2H, m), 9.30 (1H, br s), 9.41 (1H, br s), 11.18 (1H, s)
(-) ESI-MS (m / z): 580 (MH) -

実施例５３
［２−［３’−（シクロヘキシルオキシ）−４’−［［［（２−メトキシエチル）スルホニル］アミノ］カルボニル］−４−ビフェニリル］エチル］［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］カルバミン酸第三級ブチル（１９９ｍｇ）の１，４−ジオキサン（２．０ｍｌ）中の溶液に、塩化水素／１，４−ジオキサン（４Ｎ、２．０ｍｌ）を室温で加え、混合物を同温で３時間攪拌した。混合物から溶媒を減圧留去して、３−（シクロヘキシルオキシ）−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エチル］−Ｎ−［（２−メトキシエチル）スルホニル］−４−ビフェニルカルボキサミド二塩酸塩（１５３ｍｇ）を白色固形物として得た。
NMR (200 MHz, DMSO-d6, δ): 1.31-2.04 (10H, m), 3.04-3.50 (6H, m), 3.23 (3H, s), 3.72-3.84 (4H, m), 4.78-4.89 (1H, m), 5.27-5.37 (1H, m), 7.34-7.45 (4H, m), 7.68-7.79 (3H, m), 8.00 (1H, dd, J=5.5, 8.4Hz), 8.51 (1H, d, J=8.4Hz), 8.83-8.92 (2H, m), 9.33 (1H, br s), 9.45 (1H, br s), 11.19 (1H, s)
(-)ESI-MS (m/z): 580 (M-H)- Example 53
[2- [3 ′-(cyclohexyloxy) -4 ′-[[[(2-methoxyethyl) sulfonyl] amino] carbonyl] -4-biphenylyl] ethyl] [(2R) -2-hydroxy-2- (3 To a solution of tert-butyl carbamate (199 mg) in 1,4-dioxane (2.0 ml), hydrogen chloride / 1,4-dioxane (4N, 2.0 ml) was added at room temperature, The mixture was stirred at the same temperature for 3 hours. The solvent was distilled off from the mixture under reduced pressure to give 3- (cyclohexyloxy) -4 ′-[2-[[(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] ethyl] -N- [ (2-Methoxyethyl) sulfonyl] -4-biphenylcarboxamide dihydrochloride (153 mg) was obtained as a white solid.
NMR (200 MHz, DMSO-d 6 , δ): 1.31-2.04 (10H, m), 3.04-3.50 (6H, m), 3.23 (3H, s), 3.72-3.84 (4H, m), 4.78-4.89 (1H, m), 5.27-5.37 (1H, m), 7.34-7.45 (4H, m), 7.68-7.79 (3H, m), 8.00 (1H, dd, J = 5.5, 8.4Hz), 8.51 (1H , d, J = 8.4Hz), 8.83-8.92 (2H, m), 9.33 (1H, br s), 9.45 (1H, br s), 11.19 (1H, s)
(-) ESI-MS (m / z): 580 (MH) -

実施例５４
［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］［２−［４’−［［［（３−ヒドロキシプロピル）スルホニル］アミノ］カルボニル］−３’−（イソプロピルチオ）−４−ビフェニリル］エチル］カルバミン酸第三級ブチル（９４ｍｇ）の１，４−ジオキサン（１．５ｍｌ）中の溶液に、塩化水素／１，４−ジオキサン（４Ｎ、１．５ｍｌ）を室温で加え、混合物を同温で一夜攪拌した。混合物から溶媒を減圧留去して、４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エチル］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−３−（イソプロピルチオ）−４−ビフェニルカルボキサミド塩酸塩（７５ｍｇ）を白色固形物として得た。
NMR (200 MHz, DMSO-d6, δ): 1.25 (6H, d, J=6.5Hz), 1.85-1.99 (2H, m), 3.02-3.27 (6H, m), 3.49-3.58 (4H, m), 3.62-3.72 (1H, m), 4.76 (1H, br s), 4.95-5.04 (1H, m), 6.23 (1H, d, J=4Hz), 7.31-7.42 (7H, m), 7.55-7.64 (2H, m), 7.70-7.74 (3H, m), 8.92 (1H, br s), 9.26 (1H, br s), 12.14 (1H, s)
(-)ESI-MS (m/z): 555 (M-H)- Example 54
[(2R) -2-hydroxy-2-phenylethyl] [2- [4 ′-[[[(3-hydroxypropyl) sulfonyl] amino] carbonyl] -3 ′-(isopropylthio) -4-biphenylyl] ethyl Hydrogen chloride / 1,4-dioxane (4N, 1.5 ml) was added to a solution of tert-butyl carbamate (94 mg) in 1,4-dioxane (1.5 ml) at room temperature and the mixture was heated to the same temperature. And stirred overnight. The solvent was distilled off from the mixture under reduced pressure, and 4 ′-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethyl] -N-[(3-hydroxypropyl) sulfonyl] -3- (Isopropylthio) -4-biphenylcarboxamide hydrochloride (75 mg) was obtained as a white solid.
NMR (200 MHz, DMSO-d 6 , δ): 1.25 (6H, d, J = 6.5Hz), 1.85-1.99 (2H, m), 3.02-3.27 (6H, m), 3.49-3.58 (4H, m ), 3.62-3.72 (1H, m), 4.76 (1H, br s), 4.95-5.04 (1H, m), 6.23 (1H, d, J = 4Hz), 7.31-7.42 (7H, m), 7.55- 7.64 (2H, m), 7.70-7.74 (3H, m), 8.92 (1H, br s), 9.26 (1H, br s), 12.14 (1H, s)
(-) ESI-MS (m / z): 555 (MH) -

実施例５５
３−（シクロヘキシルオキシ）−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エチル］−４−ビフェニルカルボキサミド二塩酸塩（１．２ｇ）の水（５ｍｌ）中の溶液に、１Ｎ水酸化ナトリウム水溶液（３．７ｍｌ）を加えた。得られた固形物を濾過し、イソプロピルアルコールから結晶化して、３−（シクロヘキシルオキシ）−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４’−［２−［［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エチル］−４−ビフェニルカルボキサミド（１．０ｇ）を得た。
NMR (200 MHz, DMSO-d6, δ): 1.30-2.00 (12H, m), 2.80-3.10 (6H, m), 3.40-3.60 (4H, m), 4.51 (1H, m), 4.85 (1H, m), 7.10-7.40 (5H, m), 7.48 (1H, d, J=8Hz), 7.60 (1H, d, J=8Hz), 7.76 (1H, d, J=8Hz), 8.47 (1H, m), 8.57 (1H, s)
(+)ESI-MS (m/z): 582 (M+H)+ Example 55
3- (Cyclohexyloxy) -N-[(3-hydroxypropyl) sulfonyl] -4 ′-[2-[[(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] ethyl] -4 -To a solution of biphenylcarboxamide dihydrochloride (1.2 g) in water (5 ml) was added 1N aqueous sodium hydroxide solution (3.7 ml). The resulting solid was filtered and crystallized from isopropyl alcohol to give 3- (cyclohexyloxy) -N-[(3-hydroxypropyl) sulfonyl] -4 ′-[2-[[(2R) -2-hydroxy. 2- (3-Pyridyl) ethyl] amino] ethyl] -4-biphenylcarboxamide (1.0 g) was obtained.
NMR (200 MHz, DMSO-d 6 , δ): 1.30-2.00 (12H, m), 2.80-3.10 (6H, m), 3.40-3.60 (4H, m), 4.51 (1H, m), 4.85 (1H , m), 7.10-7.40 (5H, m), 7.48 (1H, d, J = 8Hz), 7.60 (1H, d, J = 8Hz), 7.76 (1H, d, J = 8Hz), 8.47 (1H, m), 8.57 (1H, s)
(+) ESI-MS (m / z): 582 (M + H) +

実施例５６
下記の化合物を実施例５５と同様の方法にしたがって得た。 Example 56
The following compound was obtained in the same manner as in Example 55.

３−（シクロヘキシルオキシ）−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４’−［３−［［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］プロピル］−４−ビフェニルカルボキサミド
NMR (200 MHz, DMSO-d6, δ): 1.30-2.00 (14H, m), 2.80-3.60 (10H, m), 4.53 (1H, m), 4.87 (1H, m), 7.10- 7.40 (5H, m), 7.49 (1H, d, J=8Hz), 7.60 (1H, d, J=8Hz), 7.79 (1H, d, J=8Hz), 8.47 (1H, m), 8.57 (1H, s)
(+)ESI-MS (m/z): 596 (M+H)+ 3- (Cyclohexyloxy) -N-[(3-hydroxypropyl) sulfonyl] -4 ′-[3-[[(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] propyl] -4 -Biphenylcarboxamide
NMR (200 MHz, DMSO-d 6 , δ): 1.30-2.00 (14H, m), 2.80-3.60 (10H, m), 4.53 (1H, m), 4.87 (1H, m), 7.10-7.40 (5H , m), 7.49 (1H, d, J = 8Hz), 7.60 (1H, d, J = 8Hz), 7.79 (1H, d, J = 8Hz), 8.47 (1H, m), 8.57 (1H, s)
(+) ESI-MS (m / z): 596 (M + H) +

Claims (5)

式[Ｉ]
Figure 0004893620
［式中、
Figure 0004893620
Figure 0004893620
 −Ｘ−は
Figure 0004893620
 （式中、−Ｙ−は結合、−Ｏ−、−ＮＨ−または−ＣＨ2−、
Ｒ4、Ｒ5およびＲ6は、水素である。）、
Ｒ1は水素、ハロゲン、ニトロまたはアミノ、
Ｒ2は水素またはＣ 1 −Ｃ 8 アルキル
Ｒ3は水素、
Ｒ7はＣ 1 −Ｃ 8 アルキル、シクロ（Ｃ 3 −Ｃ 8 ）アルキル、−Ｚ−Ｒ9または
Figure 0004893620
 （式中、−Ｚ−は−Ｏ−または−Ｓ−、
各々のＲ9は、個別にＣ 1 −Ｃ 8 アルキルまたはシクロ（Ｃ 3 −Ｃ 8 ）アルキルである。）、
Ｒ8は−Ｄ−Ｅ−Ｒ10（式中、−Ｄ−は−ＣＯＮＨＳＯ2−、
ＥはＣ 1 −Ｃ 6 アルキレン、
Ｒ10は−Ｏ−Ｒ 11
（式中、Ｒ 11は、個別に水素、Ｃ 1 −Ｃ 8 アルキルである。）である。）、
をそれぞれ意味する。］
で表される化合物またはその塩。Formula [I]
Figure 0004893620
 [Where:
Figure 0004893620
Figure 0004893620
 -X- is
Figure 0004893620
 (In the formula, —Y— represents a bond, —O—, —NH— or —CH 2 —,
R 4, R 5 and R 6 are hydrogen. ),
R 1 is hydrogen, halogen, nitro or amino,
R 2 is hydrogen or C 1 -C 8 alkyl R 3 is hydrogen,
R 7 is C 1 -C 8 alkyl, cyclo ( C 3 -C 8 ) alkyl, -ZR 9 or
Figure 0004893620
 (In the formula, -Z- represents -O- or -S-,
Each R 9 is individually C 1 -C 8 alkyl or cyclo ( C 3 -C 8 ) alkyl. ),
R 8 is in -D-E-R 10 (wherein,-D-is -CONHSO 2 -,
E is C 1 -C 6 alkylene,
R 10 is —O—R 11
( Wherein R 11 is individually hydrogen and C 1 -C 8 alkyl). ),
Means each. ]
Or a salt thereof. （１） ４'−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エチル］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−３−イソプロポキシ−４−ビフェニルカルボキサミド、
（２） ４'−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エチル］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−３−（イソプロピルチオ）−４−ビフェニルカルボキサミド、
（３） ３−（シクロヘキシルオキシ）−４'−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エチル］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４−ビフェニルカルボキサミド、
（４） ３−（シクロヘキシルオキシ）−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４'−［２−［［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エチル］−４−ビフェニルカルボキサミド、
（５） ３−（シクロヘキシルオキシ）−Ｎ−［（２−ヒドロキシエチル）スルホニル］−４'−［２−［［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エチル］−４−ビフェニルカルボキサミド、
（６） Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４'−［２−［［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エチル］−３−イソプロポキシ−４−ビフェニルカルボキサミド、
（７） ３−（シクロヘキシルオキシ）−Ｎ−［（２−ヒドロキシエチル）スルホニル］−４'−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エチル］−４−ビフェニルカルボキサミド、
（８） Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４'−［２−［［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エチル］−３−プロポキシ−４−ビフェニルカルボキサミド、
（９） ３−シクロペンチル−４'−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エトキシ］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４−ビフェニルカルボキサミド、
（１０） ４'−［２−［［（２Ｒ）−２−（４−アミノフェニル）−２−ヒドロキシエチル］アミノ］ エチル］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−３−イソブチル−４−ビフェニルカルボキサミド、
（１１） ４'−［２−［［（２Ｒ）−２−（４−アミノフェニル）−２−ヒドロキシエチル］アミノ］ エトキシ］−３−（シクロヘキシルオキシ）−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４−ビフェニルカルボキサミド、
（１２） ３−（シクロヘプチルオキシ）−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４'−［２−［［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］エチル］−４−ビフェニルカルボキサミド、
（１３） ３−（シクロヘキシルオキシ）−Ｎ−［（２−ヒドロキシエチル）スルホニル］−４'−［２−［［（１Ｓ，２Ｒ）−２−ヒドロキシ−１−メチル−２−フェニルエチル］アミノ］エチル］−４−ビフェニルカルボキサミド、
（１５） ３−（シクロヘキシルアミノ）−４'−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エトキシ］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４−ビフェニルカルボキサミド、
（１６） ３−（シクロヘキシルオキシ）−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４'−［３−［［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］プロピル］−４−ビフェニルカルボキサミド、
（１７） Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４'−［３−［［（２Ｒ）−２−ヒドロキシ−２−（３−ピリジル）エチル］アミノ］プロピル］−３−イソブトキシ−４−ビフェニルカルボキサミド、
（２０） ３−（シクロヘキシルオキシ）−Ｎ−［（３−ヒドロキシ−３−メチルブチル）スルホニル］−４'−［２−［［（２Ｒ）−２−ヒドロキシ−２−フェニルエチル］アミノ］エチル］−４−ビフェニルカルボキサミド、
（２２） ３−（シクロヘキシルオキシ）−４'−［２−［［（２Ｒ）−２−（３−フルオロフェニル）−２−ヒドロキシエチル］アミノ］エチル］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−４−ビフェニルカルボキサミド、
（２５） ４'−［［２−［［（２Ｒ）−２−（３−クロロフェニル）−２−ヒドロキシエチル］アミノ］エチル］アミノ］−Ｎ−［（３−ヒドロキシプロピル）スルホニル］−３−イソブトキシ−４−ビフェニルカルボキサミド、
よりなる群から選択される請求項１に記載の化合物またはその塩。(1) 4 ′-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethyl] -N-[(3-hydroxypropyl) sulfonyl] -3-isopropoxy-4-biphenylcarboxamide ,
(2) 4 ′-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethyl] -N-[(3-hydroxypropyl) sulfonyl] -3- (isopropylthio) -4- Biphenyl carboxamide,
(3) 3- (Cyclohexyloxy) -4 '-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethyl] -N-[(3-hydroxypropyl) sulfonyl] -4- Biphenyl carboxamide,
(4) 3- (Cyclohexyloxy) -N-[(3-hydroxypropyl) sulfonyl] -4 ′-[2-[[(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] ethyl ] -4-biphenylcarboxamide,
(5) 3- (Cyclohexyloxy) -N-[(2-hydroxyethyl) sulfonyl] -4 ′-[2-[[(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] ethyl ] -4-biphenylcarboxamide,
(6) N-[(3-hydroxypropyl) sulfonyl] -4 ′-[2-[[(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] ethyl] -3-isopropoxy- 4-biphenylcarboxamide,
(7) 3- (Cyclohexyloxy) -N-[(2-hydroxyethyl) sulfonyl] -4 ′-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethyl] -4- Biphenyl carboxamide,
(8) N-[(3-hydroxypropyl) sulfonyl] -4 ′-[2-[[(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] ethyl] -3-propoxy-4 -Biphenylcarboxamide,
(9) 3-cyclopentyl-4 ′-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethoxy] -N-[(3-hydroxypropyl) sulfonyl] -4-biphenylcarboxamide,
(10) 4 ′-[2-[[(2R) -2- (4-aminophenyl) -2-hydroxyethyl] amino] ethyl] -N-[(3-hydroxypropyl) sulfonyl] -3-isobutyl- 4-biphenylcarboxamide,
(11) 4 ′-[2-[[(2R) -2- (4-aminophenyl) -2-hydroxyethyl] amino] ethoxy] -3- (cyclohexyloxy) -N-[(3-hydroxypropyl) Sulfonyl] -4-biphenylcarboxamide,
(12) 3- (Cycloheptyloxy) -N-[(3-hydroxypropyl) sulfonyl] -4 ′-[2-[[(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] Ethyl] -4-biphenylcarboxamide,
(13) 3- (Cyclohexyloxy) -N-[(2-hydroxyethyl) sulfonyl] -4 ′-[2-[[(1S, 2R) -2-hydroxy-1-methyl-2-phenylethyl] amino ] Ethyl] -4-biphenylcarboxamide,
( 15) 3- (Cyclohexylamino) -4 '-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethoxy] -N-[(3-hydroxypropyl) sulfonyl] -4- Biphenyl carboxamide,
(16) 3- (Cyclohexyloxy) -N-[(3-hydroxypropyl) sulfonyl] -4 ′-[3-[[(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] propyl ] -4-biphenylcarboxamide,
(17) N-[(3-hydroxypropyl) sulfonyl] -4 '-[3-[[(2R) -2-hydroxy-2- (3-pyridyl) ethyl] amino] propyl] -3-isobutoxy-4 -Biphenylcarboxamide,
( 20) 3- (Cyclohexyloxy) -N-[(3-hydroxy-3-methylbutyl) sulfonyl] -4 '-[2-[[(2R) -2-hydroxy-2-phenylethyl] amino] ethyl] -4-biphenylcarboxamide,
( 22) 3- (Cyclohexyloxy) -4 '-[2-[[(2R) -2- (3-fluorophenyl) -2-hydroxyethyl] amino] ethyl] -N-[(3-hydroxypropyl) Sulfonyl] -4-biphenylcarboxamide,
( 25) 4 '-[[2-[[(2R) -2- (3-Chlorophenyl) -2-hydroxyethyl] amino] ethyl] amino] -N-[(3-hydroxypropyl) sulfonyl] -3- Isobutoxy-4-biphenylcarboxamide,
The compound or salt thereof according to claim 1 which is selected from O Li Cheng group. 医薬として許容される担体または賦形剤と共に、請求項１に記載の化合物またはその塩を有効成分として含有する医薬組成物。  A pharmaceutical composition comprising the compound according to claim 1 or a salt thereof as an active ingredient together with a pharmaceutically acceptable carrier or excipient. 請求項１に記載の化合物またはその塩を有効成分として含有するβ３アドレナリン性受容体作動薬。  A β3 adrenergic receptor agonist containing the compound according to claim 1 or a salt thereof as an active ingredient. 請求項１に記載の化合物またはその塩を有効成分として含有する、胃腸疾患、潰瘍、過活動膀胱、排尿障害、膵臓炎、肥満症または糖尿病の予防および／または治療剤。  A preventive and / or therapeutic agent for gastrointestinal diseases, ulcers, overactive bladder, dysuria, pancreatitis, obesity or diabetes, comprising the compound according to claim 1 or a salt thereof as an active ingredient.
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